Certain protein kinase inhibitors

ABSTRACT

Disclosed herein are protein kinase inhibitors, more particularly pyridazine derivatives and pharmaceutical compositions thereof, and method of use thereof.

Provided are certain compounds and/or pharmaceutically acceptable saltsthereof which can inhibit kinase activity of MEK and may be useful forthe treatment of hyper-proliferative diseases like cancer andinflammation.

Hyperproliferative diseases like cancer and inflammation are attractingthe scientific community to provide therapeutic benefits. In this regardefforts have been made to identify and target specific mechanisms whichplay a role in proliferating the diseases.

Mitogen-activated protein (MAP) kinase is relevant to many cancers. MAPkinases specifically phosphorylate serine/threonine residues ofproteins, that are activated by a variety of external stimuli (forexample, mitogens and growth factors) to manifest its actions inside thecell. The activation of MAP kinases regulates many functions of thecells with physiological implications such as cell growth, survival,apoptosis, differentiation, proliferation and gene expression (Pearson,G. et al., Endocr. Rev., 2001, 153-183).

MAP kinase pathway can be activated when a growth factor binds to itsreceptor tyrosine kinase. This interaction promotes RAS association withRAF and initiates a phosphorylation cascade through MEKs to ERKs. Thephosphorylated-ERK upon its translocation to nucleus activates severaltranscription factors to induce the expression of many genes requiredfor cell survival and proliferation (Sebolt, J. S.; Herrera, R. NatureRev. Can. 2004, 937-947).

Mitogen-activated protein/extracellular signal-regulated kinase kinase(MEK) is an attractive therapeutic target because the only knownsubstrates for MEK phosphorylation are the MAP kinases, ERK1 and ERK2.Constitutive activation of MEK/ERK was been found in pancreatic, colon,lung, kidney and ovarian primary tumor samples.

Furthermore, in additional to their potential as anti-tumor agents, MEKinhibitors are described in the art as having potential use for thetreatment of anti-inflammatory diseases (Biochem Biophy. Res. Corn.,2000, 268: 647), stroke (J. Pharmacal. Exp. Ther. 2003, 304: 172), andPain (J. Neurosci. 2002, 22:478, 2002);

Therefore, the MEK-ERK signal transduction pathway is an attractivepathway to target for therapeutic intervention. Therefore, there is aneed for MEK inhibitors that have at least one advantageous propertyselected from potency, stability, toxicity, pharmacodynamics propertiesand pharmacokinetics properties as an alternative for the treatment ofhyper-proliferative diseases like cancer and inflammation. In thisregard, a class of MEK inhibitors is provided herein.

DISCLOSURE OF THE INVENTION

Provided is at least one compound of formula (I):

and/or at least one pharmaceutically acceptable salt thereof, wherein:Z¹ and Z² are independently selected from C and N;a

moiety is

R¹, R² and R⁵ are independently selected from:

-   -   hydrogen,    -   halogen,    -   CN,    -   nitro,    -   NH₂,    -   (CH₂)_(m)-Q    -   C₁₋₆ alkyl,    -   C₂₋₆ alkenyl,    -   C₂₋₆ alkynyl,    -   C₃₋₁₀ cycloalkyl, and    -   wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₃₋₁₀        cycloalkyl are each unsubstituted or substituted with at least        one substituent, such as one, two, three, or four substituents,        independently selected from R⁷;    -   Q is selected from    -   aryl,    -   heteroaryl,    -   C₃₋₁₀ cycloalkyl, and    -   heterocyclyl,    -   wherein aryl, heteroaryl, C₃₋₁₀ cycloalkyl, and heterocyclyl are        each unsubstituted or substituted with at least one substituent,        such as one, two, three, or four substituents, independently        selected from R⁸;    -   R³, R⁴ and R⁶ are independently selected from:    -   hydrogen,    -   halogen,    -   CN,    -   nitro,    -   C₁₋₆ alkyl,    -   C₂₋₆ alkenyl, and    -   C₂₋₆ alkynyl,    -   wherein C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each        unsubstituted or substituted with at least one substituent, such        as one, two, three, or four substituents, independently selected        from R⁷;        each R⁷ is independently selected from:    -   halogen,    -   CN,    -   nitro,    -   C(═O)R^(b),    -   C(═O)OR^(b),    -   C(═O)NR^(a)R^(a),    -   C(═NR^(a))NR^(a)R^(a),    -   OR^(a),    -   OC(═O)R^(b),    -   OC(═O)NR^(a)R^(a),    -   OC₁₋₆ alkylN(R^(a))C(═O)OR^(b),    -   OC(═O)N(R^(a))S(═O)₂R^(b),    -   OC₂₋₆ alkylNR^(a)R^(a),    -   OC₂₋₆ alkylOR^(a),    -   SR^(a),    -   S(═O)R^(b),    -   S(═O)₂R^(b),    -   S(═O)₂NR^(a)R^(a),    -   S(═O)₂N(R^(a))C(═O)R^(b),    -   S(═O)₂N(R^(a))C(═O)OR^(b),    -   S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    -   (CR^(c)R^(c))_(n)NR^(a)R^(a),    -   N(R^(a))C(═O)R^(b),    -   N(R^(a))C(═O)OR^(b),    -   N(R^(a))C(═O)NR^(a)R^(a),    -   N(R^(a))C(NR^(a))NR^(a)R^(a),    -   N(R^(a))S(═O)₂R^(b),    -   N(R^(a))S(═O)₂NR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylNR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylOR^(a),    -   (CR^(c)R^(c))_(n)C₄₋₈ heterocycloalkyl,    -   (CR^(c)R^(c))_(n) aryl,    -   (CR^(c)R^(c))_(n)heteroaryl,    -   (CR^(c)R^(c))_(n)O(CR^(c)R^(c))_(n) aryl,    -   (CR^(c)R^(c))_(n)C₃₋₈ cycloalkyl,    -   (CR^(c)R^(c))_(n)C₄₋₈ heterocycloalkyl,    -   (CR^(c)R^(c))_(n)O(CR^(c)R^(c))CF₃,    -   (CR^(c)R^(c))_(n) N(CR^(c)R^(c))OR^(a),    -   (CR^(c)R^(c))_(n)N(R^(a))(CR^(c)R^(c))_(n) aryl,    -   (CR^(c)R^(c))_(n)N(R^(a))(CR^(c)R^(c))_(n) heteroaryl,    -   (CR^(c)R^(c))_(n)O(CR^(c)R^(c))_(n) heteroaryl,    -   C₁₋₆ alkyl,    -   C₂₋₆ alkenyl, and    -   C₂₋₆ alkynyl,    -   wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,        heteroaryl, C₃₋₈ cycloalkyl        and C₄₋₈ heterocycloalkyl are each unsubstituted or substituted        with at least one substituent, such as one, two, three, or four        substituents, independently selected from:    -   halogen,    -   oxo,    -   C₁₋₆ alkyl,    -   CN,    -   nitro,    -   C(═O)R^(b),    -   C(═O)OR^(b),    -   C(═O)NR^(a)R^(a),    -   C(NR^(a))NR^(a)R^(a),    -   OR^(a),    -   OC(═O)R^(b),    -   OC(═O)NR^(a)R^(a),    -   OC(═O)N(R^(a))S(═O)₂R^(b),    -   OC₂₋₆ alkylNR^(a)R^(a),    -   OC₂₋₆ alkylOR^(a),    -   SR^(a),    -   S(═O)R^(b),    -   S(═O)₂R^(b),    -   S(═O)₂NR^(a)R^(a),    -   S(═O)₂N(R^(a))C(═O)R^(b),    -   S(═O)₂N(R^(a))C(═O)OR^(b),    -   S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    -   NR^(a)R^(a),    -   N(R^(a))C(═O)R^(b),    -   N(R^(a))C(═O)OR^(b),    -   N(R^(a))C(═O)NR^(a)R^(a),    -   N(R^(a)) C(═NR^(a))NR^(a)R^(a),    -   N(R^(a)) S(═O)₂R^(b),    -   N(R^(a)) S(═O)₂NR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylNR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylOR^(a),    -   N(R^(a))(CR^(a)R^(a))_(n)—Y,    -   (CR^(a)R^(a))_(n)—Y,    -   (CR^(a)R^(a))_(n)C₃₋₈ cycloalkyl, and    -   (CR^(a)R^(a))_(n)OR^(a);        each R⁸ is independently selected from:    -   halogen,    -   oxo,    -   OCHF₂,    -   OCF₃,    -   CN,    -   nitro,    -   C(═O)R^(b),    -   C(═O)OR^(b),    -   C(═O)NR^(a)R^(a),    -   C(═NR^(a))NR^(a)R^(a),    -   OR^(a),    -   OC(═O)R^(b),    -   OC(═O)NR^(a)R^(a),    -   OC₁₋₆ alkylN(R^(a))C(═O)OR^(b),    -   OC(═O)N(R^(a))S(═O)₂R^(b),    -   OC₂₋₆ alkylNR^(a)R^(a),    -   OC₂₋₆ alkylOR^(a),    -   SR^(a),    -   S(═O)R^(b),    -   S(═O)₂R^(b),    -   S(═O)₂NR^(a)R^(a),    -   S(═O)₂N(R^(a))C(═O)R^(b),    -   S(═O)₂N(R^(a))C(═O)OR^(b),    -   S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    -   NR^(a)R^(a),    -   N(R^(a))C(═O)R^(b),    -   N(R^(a))C(═O) OR^(b),    -   N(R^(a))C(═O)NR^(a)R^(a),    -   N(R^(a))C(═NR^(a))NR^(a)R^(a),    -   N(R^(a))S(═O)₂R^(b),    -   N(R^(a))S(═O)₂NR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylNR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylOR^(a),    -   C₁₋₆ alkyl,    -   C₂₋₆ alkenyl, and    -   C₂₋₆ alkynyl,    -   wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each        unsubstituted or substituted with at least one substituent, such        as one, two, three, or four substituents, independently selected        from:        halogen,    -   CN,    -   nitro,    -   C(═O)R^(b),    -   C(═O)OR^(b),    -   C(═O)NR^(a)R^(a),    -   C(═NR^(a))NR^(a)R^(a),    -   OR^(a),    -   OC(═O)R^(b),    -   OC(═O)NR^(a)R^(a),    -   OC(═O)N(R^(a))S(═O)₂R^(b),    -   OC₂₋₆ alkylNR^(a)R^(a),    -   OC₂₋₆ alkylOR^(a),    -   SR^(a),    -   S(═O)R^(b),    -   S(═O)₂R^(b),    -   S(═O)₂NR^(a)R^(a),    -   S(═O)₂N(R^(a))C(═O)R^(b),    -   S(═O)₂N(R^(a))C(═O)OR^(b),    -   S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    -   NR^(a)R^(a),    -   N(R^(a))C(═O)R^(b),    -   N(R^(a))C(═O)OR^(b),    -   N(R^(a))C(═O)NR^(a)R^(a),    -   N(R^(a))C(═NR^(a))NR^(a)R^(a),    -   N(R^(a))S(═O)₂R^(b),    -   N(R^(a))S(═O)₂NR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylNR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylOR^(a),    -   N(R^(a))(CR^(a)R^(a))_(n)—Y,    -   (CR^(a)R^(a))_(n)—Y, and    -   (CR^(a)R^(a))_(n)OR^(a);        each R^(a) is independently selected from hydrogen and R^(b);        each R^(b) is independently selected from:    -   C₁₋₆ alkyl,    -   C₂₋₆ alkenyl,    -   C₂₋₆ alkynyl,    -   aryl,    -   heteroaryl,    -   C₃₋₈ cycloalkyl, and    -   C₄₋₈ heterocycloalkyl,    -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,        heteroaryl, C₃₋₈ cycloalkyl and C₄₋₈ heterocycloalkyl are each        unsubstituted or substituted with at least one substituent, such        as one, two, three, or four substituents, independently selected        from:    -   halogen,    -   CN,    -   OH,    -   S(═O)₂R^(b),    -   OC₂₋₆ alkylOR^(a),    -   C₁₋₄ alkyl,    -   C₁₋₃ haloalkyl,    -   OC₁₋₄ alkyl,    -   NH₂, and    -   NR^(a)R^(a);        or R^(a) and R^(b) together with the carbon atoms and/or        heteroatoms to which they are attached can form a 4-10 membered        ring containing 0, 1, 2 or 3 heteroatoms independently selected        from sulfur and nitrogen;        each R^(c) is independently selected from:    -   hydrogen,    -   OR^(a),    -   NR^(a)R^(a),    -   C₁₋₆ alkyl, and    -   CR^(c)R^(c) can form a C₃₋₈ cycloalkyl ring;        Y is selected from:    -   aryl,    -   heteroaryl,    -   C₃₋₁₀ cycloalkyl, and    -   heterocyclyl,    -   wherein aryl, heteroaryl, C₃₋₁₀ cycloalkyl, and heterocyclyl are        each unsubstituted or substituted with at least one substituent,        such as one, two, three, or four substituents, independently        selected from:    -   C₁₋₈ alkyl,    -   C₂₋₆ alkenyl,    -   C₂₋₆ alkynyl,    -   C₁₋₄ haloalkyl,    -   halogen,    -   CN,    -   nitro,    -   C(═O)R^(b),    -   C(═O)OR^(b),    -   C(═O)NR^(a)R^(a),    -   C(NR^(a))NR^(a)R^(a),    -   OR^(a),    -   OC(═O)R^(b),    -   OC(═O)NR^(a)R^(a),    -   OC(═O)N(R^(a))S(═O)₂R^(b),    -   OC₂₋₆ alkylNR^(a)R^(a),    -   OC₂₋₆ alkylOR^(a),    -   SR^(a),    -   S(═O)R^(b),    -   S(═O)₂R^(b),    -   S(═O)₂NR^(a)R^(a),    -   S(═O)₂N(R^(a))C(═O)R^(b),    -   S(═O)₂N(R^(a))C(═O) OR^(b),    -   S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    -   NR^(a)R^(a),    -   N(R^(a))C(═O)R^(b),    -   N(R_(a)) C(═O) OR^(b),    -   N(R^(a))C(═O)NR^(a)R^(a),    -   N(R^(a))C(═NR^(a))NR^(a)R^(a),    -   N(R^(a))S(═O)₂R^(b),    -   N(R^(a))S(═O)₂NR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylNR^(a)R^(a), and    -   NR^(a)C₂₋₆ alkylOR^(a);        each m is selected from 0, 1, 2, 3, and 4,        each n is independently selected from 0, 1, 2, and 3.

In yet another aspect, provided is a pharmaceutical compositioncomprising at least one compound of formula (I) and/or at least onepharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.

In yet another aspect, provided is a method for modulating MEK,comprising administering to a system or a subject in need thereof, atherapeutically effective amount of at least one compound of formula (I)and/or at least one pharmaceutically acceptable salt thereof orpharmaceutical compositions thereof, thereby modulating said MEK.

In yet another aspect, provided is a method to treat, ameliorate orprevent a condition which responds to inhibition of MEK comprisingadministering to a system or subject in need of such treatment aneffective amount of at least one compound of formula (I) and/or at leastone pharmaceutically acceptable salt thereof or pharmaceuticalcompositions thereof, and optionally in combination with a secondtherapeutic agent, thereby treating said condition.

Alternatively, provided is a use of at least one compound of formula (I)and/or at least one pharmaceutically acceptable salt thereof in themanufacture of a medicament for treating a condition mediated by MEK. Inparticular embodiments, the compounds of the disclosure may be usedalone or in combination with a second therapeutic agent to treat acondition mediated by MEK, wherein said condition is an autoimmunedisease, a transplantation disease, an infectious disease or a cellproliferative disorder.

Furthermore, provided is a method for treating a cell proliferativedisorder, comprising administering to a system or subject in need ofsuch treatment an effective amount of at least one compound of formula(I) and/or at least one pharmaceutically acceptable salt thereof orpharmaceutical compositions thereof, and optionally in combination witha second therapeutic agent, thereby treating said condition.

Alternatively, provided is a use of at least one compound of formula (I)and/or at least one pharmaceutically acceptable salt thereof in themanufacture of a medicament for treating a cell-proliferative disorder.In particular examples, the compounds of the disclosure may be usedalone or in combination with a chemotherapeutic agent to treat a cellproliferative disorder, including but not limited to, lymphoma,osteosarcoma, melanoma, or a tumor of breast, renal, prostate,colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine orgastrointestinal tumor.

In the above method(s) for using the compounds of the disclosure, atleast one compound of formula (I) and/or at least one pharmaceuticallyacceptable salt thereof may be administered to a system comprising cellsor tissues, or to a mammalian subject such as a human or animal subject.

As used herein the following definitions are applicable.

The term “alkyl” refers to both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms. Unless otherwise specified, “alkyl” refers to C₁-C₆ alkyl. Forexample, C₁-C₆, as in “C₁₋₆ alkyl” is defined to include groups having1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement. Forexample, “C₁₋₈ alkyl” includes but is not limited to methyl, ethyl,n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl,and octyl.

The term “haloalkyl” refers to both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms and being substituted with at least one halogenindependently selected from fluorine, chlorine, bromine and iodine.Unless otherwise specified, “haloalkyl” refers to C₁-C₆ haloalkyl. Forexample, C₁-C₄, as in “C₁₋₄ haloalkyl” is defined to include groupshaving 1, 2, 3, or 4 carbons in a linear or branched arrangement andbeing substituted with at least one halogen independently selected fromfluorine, chlorine, bromine and iodine.

The term “cycloalkyl” means a saturated aliphatic cyclic hydrocarbongroup having the specified number of carbon atoms. Unless otherwisespecified, “cycloalkyl” refers to C₃₋₁₀ cycloalkyl. For example,“cycloalkyl” includes but is not limited to cyclopropyl,methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, andcyclohexyl.

The term “alkenyl” refers to a non-aromatic hydrocarbon radical,straight, branched or cyclic, containing from 2 to 10 carbon atoms andat least one carbon to carbon double bond. In some embodiments, onecarbon to carbon double bond is present, and up to four non-aromaticcarbon-carbon double bonds may be present. Thus, “C₂₋₆ alkenyl” means analkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups includebut are not limited to ethenyl, propenyl, butenyl, 2-methylbutenyl andcyclohexenyl. The straight, branched or cyclic portion of the alkenylgroup may contain double bonds and may be substituted if a substitutedalkenyl group is indicated.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. In some embodiments, up to three carbon-carbontriple bonds may be present. Thus, “C₂₋₆ alkynyl” means an alkynylradical having from 2 to 6 carbon atoms. Alkynyl groups include but arenot limited to ethynyl, propynyl, butynyl, and 3-methylbutynyl. Thestraight, branched or cyclic portion of the alkynyl group may containtriple bonds and may be substituted if a substituted alkynyl group isindicated.

The term “aryl” encompasses: 5- and 6-membered carbocyclic aromaticrings, for example, benzene; bicyclic ring systems wherein at least onering is carbocyclic and aromatic, for example, naphthalene, indane, and1, 2, 3, 4-tetrahydroquinoline; and tricyclic ring systems wherein atleast one ring is carbocyclic and aromatic, for example, fluorene. Incases where the aryl substituent is bicyclic or tricyclic and at leastone ring is non-aromatic, it is understood that attachment is via thearomatic ring.

For example, aryl includes 5- and 6-membered carbocyclic aromatic ringsfused to a 5- to 7-membered heterocyclic ring containing one or moreheteroatoms selected from N, O, and S, provided that the point ofattachment is at the carbocyclic aromatic ring. Bivalent radicals formedfrom substituted benzene derivatives and having the free valences atring atoms are named as substituted phenylene radicals. Bivalentradicals derived from univalent polycyclic hydrocarbon radicals whosenames end in “-yl” by removal of one hydrogen atom from the carbon atomwith the free valence are named by adding “-idene” to the name of thecorresponding univalent radical, e.g., a naphthyl group with two pointsof attachment is termed naphthylidene. Aryl, however, does not encompassor overlap in any way with heteroaryl, separately defined below. Hence,if one or more carbocyclic aromatic rings are fused with a heterocyclicaromatic ring, the resulting ring system is heteroaryl, not aryl, asdefined herein.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine.

The term “heteroaryl” refers to 5- to 8-membered aromatic, monocyclicrings containing one or more, for example, from 1 to 4, or, in someembodiments, from 1 to 3, heteroatoms selected from N, O, and S, withthe remaining ring atoms being carbon;

8- to 12-membered bicyclic rings containing one or more, for example,from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selectedfrom N, O, and S, with the remaining ring atoms being carbon and whereinat least one heteroatom is present in an aromatic ring; and 11- to14-membered tricyclic rings containing one or more, for example, from 1to 4, or in some embodiments, from 1 to 3, heteroatoms selected from N,O, and S, with the remaining ring atoms being carbon and wherein atleast one heteroatom is present in an aromatic ring.

When the total number of S and O atoms in the heteroaryl group exceeds1, those heteroatoms are not adjacent to one another. In someembodiments, the total number of S and O atoms in the heteroaryl groupis not more than 2. In some embodiments, the total number of S and Oatoms in the aromatic heterocycle is not more than 1.

Examples of heteroaryl groups include, but are not limited to, (asnumbered from the linkage position assigned priority 1), 2-pyridyl,3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl,3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolinyl,isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl,benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl,pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and5,6,7,8-tetrahydroisoquinoline.

Further heteroaryl groups include but are not limited to pyrrolyl,isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl,benzotriazolyl, quinoxalinyl, and isoquinolinyl. As with the definitionof heterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl.

Bivalent radicals derived from univalent heteroaryl radicals whose namesend in “-yl” by removal of one hydrogen atom from the atom with the freevalence are named by adding “-idene” to the name of the correspondingunivalent radical, e.g., a pyridyl group with two points of attachmentis a pyridylidene. Heteroaryl does not encompass or overlap with aryl asdefined above.

In cases where the heteroaryl substituent is bicyclic or tricyclic andat least one ring is non-aromatic or contains no heteroatoms, it isunderstood that attachment is via the aromatic ring or via theheteroatom containing ring, respectively.

The term “heterocycle” (and variations thereof such as “heterocyclic”,or “heterocyclyl”) broadly refers to a single aliphatic ring, usuallywith 3 to 7 ring atoms, containing at least 2 carbon atoms in additionto 1-3 heteroatoms independently selected from oxygen, sulfur, andnitrogen, as well as combinations comprising at least one of theforegoing heteroatoms. “Heterocycle” also refers to 5- to 7-memberedheterocyclic ring containing one or more heteroatoms selected from N, O,and S fused with 5- and 6-membered carbocyclic aromatic ring, providedthat the point of attachment is at the heterocyclic ring. The rings maybe saturated or have one or more double bonds (i.e. partiallyunsaturated). The heterocycle can be substituted by oxo. The point ofthe attachment may be carbon or heteroatom in the heterocyclic ring,provided that attachment results in the creation of a stable structure.When the heterocyclic ring has substituents, it is understood that thesubstituents may be attached to any atom in the ring, whether aheteroatom or a carbon atom, provided that a stable chemical structureresults. Heterocycle does not overlap with heteroaryl.

Suitable heterocycles include, for example (as numbered from the linkageposition assigned priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl,2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, and 2,5-piperazinyl. Morpholinyl groupsare also contemplated, including 2-morpholinyl and 3-morpholinyl(numbered wherein the oxygen is assigned priority 1). Substitutedheterocycle also includes ring systems substituted with one or more oxomoieties, such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

As used herein, “heterocyclylalkyl” refers to alkyl substituted byheterocyclyl. When used in the phrase “heterocyclyl-C₁₋₆ alkyl”, theterm “C₁₋₆” refers to the alkyl portion of the moiety and does notdescribe the number of atoms in the heterocyclyl portion of the moiety.

For avoidance of doubt, reference, for example, to substitution ofalkyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl refers tosubstitution of each of those groups individually as well as tosubstitutions of combinations of those groups. That is, if R¹ isarylalkyl, the aryl portion may be unsubstituted or substituted with atleast one substituent, such as one, two, three, or four substituents,independently selected from R⁸ and the alkyl portion may also beunsubstituted or substituted with at least one substituent, such as one,two, three, or four substituents, independently selected from R⁷.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases may be selected, for example, from aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,manganic, manganous, potassium, sodium, and zinc salts. Further, forexample, the pharmaceutically acceptable salts derived from inorganicbases may be selected from ammonium, calcium, magnesium, potassium, andsodium salts. Salts in the solid form may exist in one or more crystalstructures, and may also be in the form of hydrates. Salts derived frompharmaceutically acceptable organic non-toxic bases may be selected, forexample, from salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine, andtripropylamine, tromethamine.

When the compound disclosed herein is basic, salts may be prepared usingat least one pharmaceutically acceptable non-toxic acid, selected frominorganic and organic acids. Such acid may be selected, for example,from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,and p-toluenesulfonic acids. In some embodiments, such acid may beselected, for example, from citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, fumaric, and tartaric acids.

The term “protecting group” or “Pg” refers to a substituent that can becommonly employed to block or protect a certain functionality whilereacting other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include but are not limited to acetyl,trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includebut are not limited to acetyl and silyl. A “carboxy-protecting group”refers to a substituent of the carboxy group that blocks or protects thecarboxy functionality. Common carboxy-protecting groups include—CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991.

The terms “administration of” and or “administering” at least onecompound and/or at least one pharmaceutically acceptable salt should beunderstood to mean providing at least one compound and/or at least onepharmaceutically acceptable salt thereof to the individual in recognizedneed of treatment.

The term “effective amount” means the amount of the at least onecompound and/or at least one pharmaceutically acceptable salt that willelicit the biological or medical response of a tissue, system, animal orhuman that is being sought by the researcher, veterinarian, medicaldoctor or other clinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to a pharmaceutical composition is intended to encompass aproduct comprising the active ingredient (s), and the inert ingredient(s) that make up the carrier, as well as any product which results,directly or indirectly, from combination, complexation or aggregation ofany two or more of the ingredients, or from dissociation of one or moreof the ingredients, or from other types of reactions or interactions ofone or more of the ingredients.

The term “pharmaceutically acceptable” it is meant compatible with theother ingredients of the formulation and not unacceptably deleterious tothe recipient thereof.

In one embodiment, disclosed herein is at least one compound of formula(I):

and/or at least one pharmaceutically acceptable salt thereof, wherein:Z¹ and Z² are independently selected from C and N;a

moiety is

R¹, R², and R⁵ are independently selected from:

-   -   hydrogen,    -   halogen,    -   CN,    -   nitro,    -   NH₂,    -   (CH₂)_(m)-Q,    -   C₁₋₆ alkyl,    -   C₂₋₆ alkenyl,    -   C₂₋₆ alkynyl,    -   C₃₋₁₀ cycloalkyl, and    -   wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₃₋₁₀        cycloalkyl are each unsubstituted or substituted with at least        one substituent, such as one, two, three, or four substituents,        independently selected from R⁷;        Q is selected from    -   aryl,    -   heteroaryl,    -   C₃₋₁₀ cycloalkyl, and    -   heterocyclyl,    -   wherein aryl, heteroaryl, C3-10 cycloalkyl, and heterocyclyl are        each unsubstituted or substituted with at least one substituent,        such as one, two, three, or four substituents, independently        selected from R8;        R³, R⁴, and R⁶ are independently selected from:    -   hydrogen,    -   halogen,    -   CN,    -   nitro,    -   C₁₋₆ alkyl,    -   C₂₋₆ alkenyl, and    -   C₂₋₆ alkynyl,    -   wherein C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each        unsubstituted or substituted with at least one substituent, such        as one, two, three, or four substituents, independently selected        from R⁷;        each R⁷ is independently selected from:    -   halogen,    -   CN,    -   nitro,    -   C(═O)R^(b),    -   C(═O)OR^(b),    -   C(═O)NR^(a)R^(a),    -   C(═NR^(a))NR^(a)R^(a),    -   OR^(a),    -   OC(═O)R^(b),    -   OC(═O)NR^(a)R^(a),    -   OC₁₋₆ alkylN(R^(a))C(═O)OR^(b),    -   OC(═O)N(R^(a))S(═O)₂R^(b),    -   OC₂₋₆ alkylNR^(a)R^(a),    -   OC₂₋₆ alkylOR^(a),    -   SR^(a),    -   S(═O)R^(b),    -   S(═O)₂R^(b),    -   S(═O)₂NR^(a)R^(a),    -   S(═O)₂N(R^(a))C(═O)R^(b),    -   S(═O)₂N(R^(a))C(═O) OR^(b),    -   S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    -   (CR^(c)R^(c))_(n)NR^(a)R^(a),    -   N(R^(a))C(═O)R^(b),    -   N(R^(a)) C(═O) OR^(b),    -   N(R^(a))C(═O)NR^(a)R^(a),    -   N(R^(a))C(NR^(a))NR^(a)R^(a),    -   N(R^(a))S(═O)₂R^(b),    -   N(R^(a))S(═O)₂NR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylNR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylOR^(a),    -   (CR^(c)R^(c))_(n)C₄₋₈ heterocycloalkyl,    -   (CR^(c)R^(c))_(n)aryl,    -   (CR^(c)R^(c))_(n)heteroaryl,    -   (CR^(c)R^(c))_(n)O(CR^(c)R^(c))_(n)aryl,    -   (CR^(c)R^(c))_(n)C₃₋₈ cycloalkyl,    -   (CR^(c)R^(c))_(n)C₄₋₈ heterocycloalkyl,    -   (CR^(c)R^(c))_(n)O(CR^(c)R^(c))_(n)CF₃,    -   (CR^(c)R^(c))_(n) N(CR^(c)R^(c))_(n)OR^(a),    -   (CR^(c)R^(c))_(n)N(R^(a))(CR^(c)R^(c))_(n)aryl,    -   (CR^(c)R^(c))_(n)N(R^(a))(CR^(c)R^(c))_(n)heteroaryl,    -   (CR^(c)R^(c))_(n)O(CR^(c)R^(c))_(n)heteroaryl,    -   C₁₋₆ alkyl,    -   C₂₋₆ alkenyl, and    -   C₂₋₆ alkynyl,    -   wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,        heteroaryl, C₃₋₈ cycloalkyl and C₄₋₈ heterocycloalkyl are each        unsubstituted or substituted with at least one substituent, such        as one, two, three, or four substituents, independently selected        from:    -   halogen,    -   oxo,    -   C₁₋₆ alkyl,    -   CN,    -   nitro,    -   C(═O)R^(b),    -   C(═O)OR^(b),    -   C(═O)NR^(a)R^(a),    -   C(NR^(a))NR^(a)R^(a),    -   OR^(a),    -   OC(═O)R^(b),    -   OC(═O)NR^(a)R^(a),    -   OC(═O)N(R^(a))S(═O)₂R^(b),    -   OC₂₋₆ alkylNR^(a)R^(a),    -   OC₂₋₆ alkylOR^(a),    -   SR^(a),    -   S(═O)R^(b),    -   S(═O)₂R^(b),    -   S(═O)₂NR^(a)R^(a),    -   S(═O)₂N(R^(a))C(═O)R^(b),    -   S(═O)₂N(R^(a))C(═O) OR^(b),    -   S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    -   NR^(a)R^(a),    -   N(R^(a))C(═O)R^(b),    -   N(R^(a))C(═O)OR^(b),    -   N(R^(a))C(═O)NR^(a)R^(a),    -   N(R^(a))C(═NR^(a))NR^(a)R^(a),    -   N(R^(a))S(═O)₂R^(b),    -   N(R^(a))S(═O)₂NR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylNR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylOR^(a),    -   N(R^(a))(CR^(a)R^(a))_(n)—Y,    -   (CR^(a)R^(a))_(n)—Y,    -   (CR^(a)R^(a))_(n)C₃₋₈ cycloalkyl, and    -   (CR^(a)R^(a))_(n)OR^(a);    -   each R⁸ is independently selected from:    -   halogen,    -   oxo,    -   OCHF₂,    -   OCF₃,    -   CN,    -   nitro,    -   C(═O)R^(b),    -   C(═O)OR^(b),    -   C(═O)NR^(a)R^(a),    -   C(═NR^(a))NR^(a)R^(a),    -   OR^(a),    -   OC(═O)R^(b),    -   OC(═O)NR^(a)R^(a),    -   OC₁₋₆ alkylN(R^(a))C(═O)OR^(b),    -   OC(═O)N(R^(a))S(═O)₂R^(b),    -   OC₂₋₆ alkylNR^(a)R^(a),    -   OC₂₋₆ alkylOR^(a),    -   SR^(a),    -   S(═O)R^(b),    -   S(═O)₂R^(b),    -   S(═O)₂NR^(a)R^(a),    -   S(═O)₂N(R^(a))C(═O)R^(b),    -   S(═O)₂N(R^(a))C(═O)OR^(b),    -   S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    -   NR^(a)R^(a),    -   N(R^(a))C(═O)R^(b),    -   N(R^(a)) C(═O) OR^(b),    -   N(R^(a))C(═O)NR^(a)R^(a),    -   N(R^(a))C(═NR^(a))NR^(a)R^(a),    -   N(R^(a))S(═O)₂R^(b),    -   N(R^(a))S(═O)₂NR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylNR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylOR^(a),    -   C₁₋₆ alkyl,    -   C₂₋₆ alkenyl, and    -   C₂₋₆ alkynyl,    -   wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each        unsubstituted or substituted with at least one substituent, such        as one, two, three, or four substituents, independently selected        from:    -   halogen,    -   CN,    -   nitro,    -   C(═O)R^(b),    -   C(═O)OR^(b),    -   C(═O)NR^(a)R^(a),    -   C(NR^(a))NR^(a)R^(a),    -   OR^(a),    -   OC(═O)R^(b),    -   OC(═O)NR^(a)R^(a),    -   OC(═O)N(R^(a)) S(═O)₂R^(b),    -   OC₂₋₆ alkylNR^(a)R^(a),    -   OC₂₋₆ alkylOR^(a),    -   SR^(a),    -   S(═O)R^(b),    -   S(═O)₂R^(b),    -   S(═O)₂NR^(a)R^(a),    -   S(═O)₂N(R^(a)) C(═O)R^(b),    -   S(═O)₂N(R^(a))C(═O) OR^(b),    -   S(═O)₂N(R^(a)) C(═O)NR^(a)R^(a),    -   NR^(a)R^(a),    -   N(R^(a))C(═O)R^(b),    -   N(R^(a)) C(═O) OR^(b),    -   N(R^(a))C(═O)NR^(a)R^(a),    -   N(R^(a))C(═NR^(a))NR^(a)R^(a),    -   N(R^(a))S(═O)₂R^(b),    -   N(R^(a))S(═O)₂NR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylNR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylOR^(a),    -   N(R^(a))(CR^(a)R^(a))_(n)—Y,    -   (CR^(a)R^(a))_(n)—Y, and    -   (CR^(a)R^(a))_(n)OR^(a);        each R^(a) is independently selected from hydrogen and R^(b);        each R^(b) is independently selected from:    -   C₁₋₆ alkyl,    -   C₂₋₆ alkenyl,    -   C₂₋₆ alkynyl,    -   aryl,    -   heteroaryl,    -   C₃₋₈ cycloalkyl, and    -   C₄₋₈ heterocycloalkyl,    -   wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,        heteroaryl, C₃₋₈ cycloalkyl and C₄₋₈ heterocycloalkyl are each        unsubstituted or substituted with at least one substituent, such        as one, two, three, or four substituents, independently selected        from:    -   halogen,    -   CN,    -   OH,    -   S(═O)₂R^(b),    -   OC₂₋₆ alkylOR^(a),    -   C₁₋₄ alkyl,    -   C₁₋₃ haloalkyl,    -   OC₁₋₄ alkyl,    -   NH₂, and    -   NR^(a)R^(a);        or R^(a) and R^(b) together with the carbon atoms and/or        heteroatoms to which they are attached can form a 4-10 membered        ring containing 0, 1, 2 or 3 heteroatoms independently selected        from sulfur and nitrogen;        each R^(c) is independently selected from:    -   hydrogen,    -   OR^(a),    -   NR^(a)R^(a),    -   C₁₋₆ alkyl, and    -   CR^(c)R^(c) can form a C₃₋₈ cycloalkyl ring;        Y is selected from:    -   aryl,    -   heteroaryl,    -   C₃₋₁₀ cycloalkyl, and    -   heterocyclyl,    -   wherein aryl, heteroaryl, C₃₋₁₀ cycloalkyl, and heterocyclyl are        each unsubstituted or substituted with at least one substituent,        such as one, two, three, or four substituents, independently        selected from:    -   C₁₋₈ alkyl,    -   C₂₋₆ alkenyl,    -   C₂₋₆ alkynyl,    -   C₁₋₄ haloalkyl,    -   halogen,    -   CN,    -   nitro,    -   C(═O)R^(b),    -   C(═O)OR^(b),    -   C(═O)NR^(a)R^(a),    -   C(NR^(a))NR^(a)R^(a),    -   OR^(a),    -   OC(═O)R^(b),    -   OC(═O)NR^(a)R^(a),    -   OC(═O)N(R^(a))S(═O)₂R^(b),    -   OC₂₋₆ alkylNR^(a)R^(a),    -   OC₂₋₆ alkylOR^(a),    -   SR^(a),    -   S(═O)R^(b),    -   S(═O)₂R^(b),    -   S(═O)₂NR^(a)R^(a),    -   S(═O)₂N(R^(a))C(═O)R^(b),    -   S(═O)₂N(R^(a))C(═O) OR^(b),    -   S(═O)₂N(R^(a))C(═O)NR^(a)R^(a),    -   NR^(a)R^(a),    -   N(R^(a))C(═O)R^(b),    -   N(R_(a))C(═O)OR^(b),    -   N(R^(a))C(═O)NR^(a)R^(a),    -   N(R^(a))C(═NR^(a))NR^(a)R^(a),    -   N(R^(a))S(═O)₂R^(b),    -   N(R^(a))S(═O)₂NR^(a)R^(a),    -   NR^(a)C₂₋₆ alkylNR^(a)R^(a), and    -   NR^(a)C₂₋₆ alkylOR^(a);        each m is selected from 0, 1, 2, 3, and 4,        each n is independently selected from 0, 1, 2, and 3.

In some embodiments,

a moiety is

In some embodiments, R⁶ is hydrogen.

In some embodiments, R¹ is selected from hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl and C₃₋₁₀ cycloalkyl, wherein alkyl, alkenyl and cycloalkyl areeach unsubstituted or substituted with at least one substituent, such asone, two, three, or four substituents, independently selected fromhalogen and OR^(a), wherein R^(a) is independently selected fromhydrogen and C₁₋₆ alkyl.

In some embodiments, R¹ is methyl, ethyl, propyl, isopropyl, allyl, orcyclopropyl, each is independently unsubstituted or substituted with atleast one substituent, such as one, two, three, or four substituents,independently selected from halogen and OR^(a), wherein R^(a) isindependently selected from hydrogen and C₁₋₆ alkyl. In someembodiments, R¹ is methyl, ethyl, propyl, isopropyl, allyl, orcyclopropyl, each is independently unsubstituted or substituted with atleast one substituent, such as one, two, three, or four substituents,independently selected from halogen and OR^(a), wherein R^(a) isindependently selected from hydrogen and methyl. In some embodiments, R¹is methyl, ethyl, propyl, isopropyl, allyl, cyclopropyl, 2-fluoroethyl,2,2-difluoroethyl, 2,3-dihydroxypropyl, or 2-methylxoyethyl.

In some embodiments, R² is selected from hydrogen, halogen, CN,(CH₂)_(m)-Q, C₁₋₆ alkyl, or C₃₋₈ cycloalkyl, wherein alkyl andcycloalkyl are independently unsubstituted or substituted with at leastone substituent, such as one, two, three, or four substituents,independently selected from R⁷, R⁷ is as described above.

In some embodiments, R² is selected from (CH₂)_(m)-Q, wherein m is 0,and Q is selected from aryl and heteroaryl, wherein aryl and heteroarylare each unsubstituted or substituted with at least one substituent,such as one, two, three, or four substituents, independently selectedfrom R⁸, R⁸ is as described above.

In some embodiments, R² is selected from (CH₂)_(m)-Q, wherein m is 0,and Q is selected from aryl, wherein aryl is unsubstituted orsubstituted with at least one substituent, such as one, two, three, orfour substituents, independently selected from R⁸, R⁸ is as describedabove.

In some embodiments, R² is selected from (CH₂)_(m)-Q, wherein m is 0,and Q is phenyl, which is unsubstituted or substituted with at least onesubstituent, such as one, two, three, or four substituents,independently selected from R⁸, R⁸ is as described above.

In some embodiments, R² is selected from (CH₂)_(m)-Q, wherein m is 0,and Q is phenyl which is unsubstituted or substituted with at least onesubstituent, such as one, two, three, or four substituents,independently selected from R⁸, wherein R⁸ is independently selectedfrom NR^(a)R^(a), N(R^(a))C(═O)R^(b), N(R^(a))C(═O)OR^(b),N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))S(═O)₂R^(b),N(R^(a))S(═O)₂NR^(a)R^(a), R^(a) and R^(b) are as described above.

In some embodiments, R² is selected from (CH₂)_(m)-Q, wherein m is 0,and Q is phenyl which is unsubstituted or substituted with at least onesubstituent, such as one, two, three, or four substituents,independently selected from R⁸, wherein R⁸ is independently selectedfrom N(R^(a))C(═O)R^(b), N(R^(a))S(═O)₂R^(b), R^(a) and R^(b) are asdescribed above. In some embodiments, R² is selected from (CH₂)_(m)-Q,wherein m is 0, and Q is phenyl which is unsubstituted or substitutedwith at least one substituent, such as one, two, three, or foursubstituents, independently selected from R⁸, wherein R⁸ isindependently selected from N(R^(a))C(═O)R^(b), N(R^(a))S(═O)₂R^(b),wherein R^(a) is hydrogen or methyl, and R^(b) is independently selectedfrom methyl, ethyl, isopropyl and cyclopropyl.

In some embodiments, R² is selected from (CH₂)_(m)-Q, wherein m is 0,and Q is phenyl which is unsubstituted or substituted with at least onesubstituent, such as one, two, three, or four substituents,independently selected from R⁸, wherein R⁸ is independently selectedfrom N(R^(a))C(═O)R^(b), N(R^(a))S(═O)₂R^(b), wherein R^(a) and R^(b)together with the carbon atoms and/or heteroatoms to which they areattached form a 5-6 membered ring containing 0, 1, 2 or 3 heteroatomsindependently selected from sulfur and nitrogen. In some embodiments, Qis phenyl which is unsubstituted or substituted with at least onesubstituent, such as one, two, three, or four substituents,independently selected from R⁸, wherein R⁸ is independently selectedfrom 2-oxopyrrolidin-1-yl and 1,1-dioxidoisothiazolidin-2-yl.

In some embodiments, R³ is C₁₋₆ alkyl.

In some embodiments, R³ is methyl.

In some embodiments, R⁴ is selected from hydrogen, halogen, CN and C₁₋₆alkyl.

In some embodiments, R⁴ is selected from halogen and methyl.

In some embodiments, R⁴ is fluorine or chlorine.

In some embodiments, R⁵ is (CH₂)_(m)-Q, wherein m and Q are as describedabove.

In some embodiments, R⁵ is (CH₂)_(m)-Q, wherein m is 0 and Q are asdescribed above.

In some embodiments, R⁵ is (CH₂)_(m)-Q, wherein m is 0 and Q is arylwhich is unsubstituted or substituted with at least one substituent,such as one, two, three, or four substituents, independently selectedfrom R⁸.

In some embodiments, R⁵ is (CH₂)_(m)-Q, wherein m is 0 and Q is phenylwhich is unsubstituted or substituted with at least one substituent,such as one, two, three, or four substituents, independently selectedfrom halogen.

In some embodiments, R⁵ is 2-fluoro-4-iodophenyl or4-bromo-2-fluorophenyl.

Also provided is at least one compound, selected from:

-   N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide,-   N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propionamide,-   N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)isobutyramide,-   N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanecarboxamide,-   N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide,-   N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenypethanesulfonamide,-   N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide,-   N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propionamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenypisobutyramide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanecarboxamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenypethanesulfonamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-6-propyl-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-(2-methoxyethyl)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-(2-fluoroethyl)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(6-(2,2-difluoroethyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide,-   N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide,-   N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide,-   N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide,-   N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide,-   N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propionamide,-   N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanecarboxamide,-   N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide,-   N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenypethanesulfonamide,-   N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide,-   N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide,-   N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)isobutyramide,-   N-(3-(6-allyl-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide,-   N-(3-(6-allyl-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide,-   N-(3-(6-allyl-3-chloro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide,-   N-(3-(3-chloro-6-(2,3-dihydroxypropyl)-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide,-   N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide,-   N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propionamide,-   N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanecarboxamide,-   N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide,-   N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenypethanesulfonamide,-   N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide,-   N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide,-   N-(3-(6-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylmethanesulfonamide,-   N-(3-(6-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylpropane-2-sulfonamide,-   N-(3-(6-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylcyclopropanesulfonamide,-   N-(3-(3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylmethanesulfonamide,-   N-(3-(3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylpropane-2-sulfonamide,-   N-(3-(3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylcyclopropanesulfonamide,-   6-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-8-(3-(2-oxopyrrolidin-1-yl)phenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione,-   3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-8-(3-(2-oxopyrrolidin-1-yl)phenyl)pyrido[2,3-d]pyridazine-2,    5(1H,6H)-dione,-   6-cyclopropyl-8-(3-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione,    and-   8-(3-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt.

In another of its aspects, there is provided a pharmaceuticalcomposition comprising as an active ingredient a compound according toany one of the above embodiments and variations. In one particularvariation, the composition is a solid formulation adapted for oraladministration. In another particular variation, the composition is aliquid formulation adapted for oral administration. In yet anotherparticular variation, the composition is a tablet. In still anotherparticular variation, the composition is a liquid formulation adaptedfor parenteral administration.

In another of its aspects, there is provided a pharmaceuticalcomposition comprising a compound according to any one of the aboveembodiments and variations, wherein the composition is adapted foradministration by a route selected from the group consisting of orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, and intrathecally.

In yet another of its aspects, there is provided a kit comprising acompound of any one of the above embodiments and variations; andinstructions which comprise one or more forms of information selectedfrom the group consisting of indicating a disease state for which thecomposition is to be administered, storage information for thecomposition, dosing information and instructions regarding how toadminister the composition. In one particular variation, the kitcomprises the compound in a multiple dose form.

In still another of its aspects, there is provided an article ofmanufacture comprising a compound of any one of the above embodimentsand variations; and packaging materials. In one variation, the packagingmaterial comprises a container for housing the compound. In oneparticular variation, the container comprises a label indicating one ormore members of the group consisting of a disease state for which thecompound is to be administered, storage information, dosing informationand/or instructions regarding how to administer the compound. In anothervariation, the article of manufacture comprises the compound in amultiple dose form.

In a further of its aspects, there is provided a therapeutic methodcomprising administering a compound of any one of the above embodimentsand variations to a subject.

In another of its aspects, there is provided a method of inhibiting aMitogen-Activated Protein Kinase comprising contacting the MEK with acompound of any one of the above embodiments and variations.

In yet another of its aspects, there is provided a method of inhibitinga Mitogen-activated protein/extracellular signal-regulated kinase kinase(MEK) comprising causing a compound of any one of the above embodimentsand variations to be present in a subject in order to inhibit the MEK invivo.

In a further of its aspects, there is provided a method of inhibitingMitogen-activated protein/extracellular signal-regulated kinase kinase(MEK) comprising administering a first compound to a subject that isconverted in vivo to a second compound wherein the second compoundinhibits the MEK in vivo, the second compound being a compound accordingto any one of the above embodiments and variations.

In another of its aspects, there is provided a method of treating adisease state for which a Mitogen-activated protein/extracellularsignal-regulated kinase kinase (MEK) possesses activity that contributesto the pathology and/or symptomology of the disease state, the methodcomprising causing a compound of any one of the above embodiments andvariations to be present in a subject in a therapeutically effectiveamount for the disease state.

In yet another of its aspects, there is provided a method of treating adisease state for which a Mitogen-activated protein/extracellularsignal-regulated kinase kinase (MEK) possesses activity that contributesto the pathology and/or symptomology of the disease state, the methodcomprising administering a compound of any one of the above embodimentsand variations to a subject, wherein the compound is present in thesubject in a therapeutically effective amount for the disease state.

In a further of its aspects, there is provided a method of treating adisease state for which a Mitogen-activated protein/extracellularsignal-regulated kinase kinase (MEK) possesses activity that contributesto the pathology and/or symptomology of the disease state, the methodcomprising administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibits theMEK in vivo. It is noted that the compounds of the present invention maybe the first or second compounds.

In one variation of each of the above methods the disease state isselected from the group consisting of cancerous hyperproliferativedisorders (e.g., brain, lung, squamous cell, bladder, gastric,pancreatic, breast, head, neck, renal, kidney, ovarian, prostate,colorectal, epidermoid, esophageal, testicular, gynecological or thyroidcancer); non-cancerous hyperproliferative disorders (e.g., benignhyperplasia of the skin (e.g., psoriasis), restenosis, and benignprostatic hypertrophy (BPH)); pancreatitis; kidney disease; pain;preventing blastocyte implantation; treating diseases related tovasculogenesis or angiogenesis (e.g., tumor angiogenesis, acute andchronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, exzema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer); asthma;neutrophil chemotaxis (e.g., reperfusion injury in myocardial infarctionand stroke and inflammatory arthritis); septic shock; T-cell mediateddiseases where immune suppression would be of value (e.g., theprevention of organ transplant rejection, graft versus host disease,lupus erythematosus, multiple sclerosis, and rheumatoid arthritis);atherosclerosis; inhibition of keratinocyte responses to growth factorcocktails; chronic obstructive pulmonary disease (COPD) and otherdiseases.

In another variation of each of the above methods, the Mitogen-activatedprotein/extracellular signal-regulated kinase kinase (MEK) is MEK1. Instill another variation of each of the above methods, theMitogen-activated protein/extracellular signal-regulated kinase kinase(MEK) is MEK2.

In another of its aspects, there is provided a method of inhibiting anExtracellular Regulated Kinase (ERK) comprising contacting the ERK witha compound of any of the above embodiments and variations.

In still another of its aspects, there is provided a method ofinhibiting Extracellular Regulated Kinase (ERK) comprising causing acompound of any of the above embodiments and variations to be present ina subject in order to inhibit the ERK in vivo.

In yet another of its aspects, there is provided a method of inhibitingExtracellular Regulated Kinase (ERK) comprising administering a firstcompound to a subject that is converted in vivo to a second compoundwherein the second compound inhibits the ERK in vivo, the secondcompound being a compound according to any of the above embodiments andvariations.

In one variation of the above methods, the Extracellular RegulatedKinase (ERK) is ERK 1. In another variation of the above methods, theExtracellular Regulated Kinase (ERK) is ERK2.

In another of its aspects, there is provided a method of treating adisease state for which a mutation in the Mek gene contributes to thepathology and/or symptomology of the disease state including, forexample, melanomas, lung cancer, colon cancer and other tumor types.

In still another of its aspects, the present invention relates to theuse of a compound of any of the above embodiments and variations as amedicament. In yet another of its aspects, the present invention relatesto the use of a compound according to any one of the above embodimentsand variations in the manufacture of a medicament for inhibiting aMitogen-activated protein/extracellular signal-regulated kinase kinase(MEK).

In a further of its aspects, the present invention relates to the use ofa compound according to any one of the above embodiments and variationsin the manufacture of a medicament for treating a disease state forwhich a Mitogen-activated protein/extracellular signal-regulated kinasekinase (MEK) possesses activity that contributes to the pathology and/orsymptomology of the disease state.

Administration and Pharmaceutical Compositions

In general, compounds of the disclosure will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors known tothose of ordinary skill in the art. For example, for the treatment ofneoplastic diseases and immune system disorders, the required dosagewill also vary depending on the mode of administration, the particularcondition to be treated and the effect desired.

In general, satisfactory results are indicated to be obtainedsystemically at daily dosages of from about 0.001 to about 100 mg/kg perbody weight, or particularly, from about 0.03 to 2.5 mg/kg per bodyweight. An indicated daily dosage in the larger mammal, e.g. humans, maybe in the range from about 0.5 mg to about 2000 mg, or moreparticularly, from about 0.5 mg to about 100 mg, convenientlyadministered, for example, in divided doses up to four times a day or inretard form. Suitable unit dosage forms for oral administration comprisefrom ca. 1 to 50 mg active ingredient.

Compounds of the disclosure may be administered as pharmaceuticalcompositions by any conventional route; for example, enterally, e.g.,orally, e.g., in the form of tablets or capsules; parenterally, e.g., inthe form of injectable solutions or suspensions; or topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form.

Pharmaceutical compositions comprising a compound of the presentdisclosure in free form or in a pharmaceutically acceptable salt form inassociation with at least one pharmaceutically acceptable carrier ordiluent may be manufactured in a conventional manner by mixing,granulating, coating, dissolving or lyophilizing processes. For example,pharmaceutical compositions comprising a compound of the disclosure inassociation with at least one pharmaceutical acceptable carrier ordiluent may be manufactured in conventional manner by mixing with apharmaceutically acceptable carrier or diluent. Unit dosage forms fororal administration contain, for example, from about 0.1 mg to about 500mg of active substance.

In one embodiment, the pharmaceutical compositions are solutions of theactive ingredient, including suspensions or dispersions, such asisotonic aqueous solutions. In the case of lyophilized compositionscomprising the active ingredient alone or together with a carrier suchas mannitol, dispersions or suspensions can be made up before use. Thepharmaceutical compositions may be sterilized and/or contain adjuvants,such as preserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure and/or buffers.Suitable preservatives include but are not limited to antioxidants suchas ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.The solutions or suspensions may further comprise viscosity-increasingagents, including but not limited to, sodium carboxymethylcellulose,carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, orsolubilizers, e.g. Tween 80 (polyoxyethylene(20)sorbitan mono-oleate).

Suspensions in oil may comprise as the oil component the vegetable,synthetic, or semi-synthetic oils customary for injection purposes.Examples include liquid fatty acid esters that contain as the acidcomponent a long-chained fatty acid having from 8 to 22 carbon atoms, orin some embodiments, from 12 to 22 carbon atoms. Suitable liquid fattyacid esters include but are not limited to lauric acid, tridecylic acid,myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearicacid, arachidic acid, behenic acid or corresponding unsaturated acids,for example oleic acid, elaidic acid, erucic acid, brassidic acid andlinoleic acid, and if desired, may contain antioxidants, for examplevitamin E, 3-carotene or 3,5-di-tert-butyl-hydroxytoluene. The alcoholcomponent of these fatty acid esters may have six carbon atoms and maybe monovalent or polyvalent, for example a mono-, di- or trivalent,alcohol. Suitable alcohol components include but are not limited tomethanol, ethanol, propanol, butanol or pentanol or isomers thereof;glycol and glycerol.

Other suitable fatty acid esters include but are not limitedethyl-oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL® M2375, (polyoxyethylene glycerol), LABRAFIL® M 1944 CS (unsaturatedpolyglycolized glycerides prepared by alcoholysis of apricot kernel oiland comprising glycerides and polyethylene glycol ester), LABRASOL™(saturated polyglycolized glycerides prepared by alcoholysis of TCM andcomprising glycerides and polyethylene glycol ester; all available fromGaKefosse, France), and/or MIGLYOL® 812 (triglyceride of saturated fattyacids of chain length C8 to C12 from Hüls AG, Germany), and vegetableoils such as cottonseed oil, almond oil, olive oil, castor oil, sesameoil, soybean oil, or groundnut oil.

Pharmaceutical compositions for oral administration may be obtained, forexample, by combining the active ingredient with one or more solidcarriers, and if desired, granulating a resulting mixture, andprocessing the mixture or granules by the inclusion of additionalexcipients, to form tablets or tablet cores.

Suitable carriers include but are not limited to fillers, such assugars, for example lactose, saccharose, mannitol or sorbitol, cellulosepreparations, and/or calcium phosphates, for example tricalciumphosphate or calcium hydrogen phosphate, and also binders, such asstarches, for example corn, wheat, rice or potato starch,methylcellulose, hydroxypropyl methylcellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired,disintegrators, such as the above-mentioned starches, carboxymethylstarch, crosslinked polyvinylpyrrolidone, alginic acid or a saltthereof, such as sodium alginate. Additional excipients include flowconditioners and lubricants, for example silicic acid, talc, stearicacid or salts thereof, such as magnesium or calcium stearate, and/orpolyethylene glycol, or derivatives thereof.

Tablet cores may be provided with suitable, optionally enteric, coatingsthrough the use of, inter alia, concentrated sugar solutions which maycomprise gum arable, talc, polyvinylpyrrolidone, polyethylene glycoland/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures, or, for the preparation of entericcoatings, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Dyes or pigments may be added to the tablets or tablet coatings, forexample for identification purposes or to indicate different doses ofactive ingredient.

Pharmaceutical compositions for oral administration may also includehard capsules comprising gelatin or soft-sealed capsules comprisinggelatin and a plasticizer, such as glycerol or sorbitol. The hardcapsules may contain the active ingredient in the form of granules, forexample in admixture with fillers, such as corn starch, binders, and/orglidants, such as talc or magnesium stearate, and optionallystabilizers. In soft capsules, the active ingredient may be dissolved orsuspended in suitable liquid excipients, such as fatty oils, paraffinoil or liquid polyethylene glycols or fatty acid esters of ethylene orpropylene glycol, to which stabilizers and detergents, for example ofthe polyoxyethylene sorbitan fatty acid ester type, may also be added.

Pharmaceutical compositions suitable for rectal administration are, forexample, suppositories comprising a combination of the active ingredientand a suppository base. Suitable suppository bases are, for example,natural or synthetic triglycerides, paraffin hydrocarbons, polyethyleneglycols or higher alkanols.

Pharmaceutical compositions suitable for parenteral administration maycomprise aqueous solutions of an active ingredient in water-solubleform, for example of a water-soluble salt, or aqueous injectionsuspensions that contain viscosity-increasing substances, for examplesodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired,stabilizers. The active ingredient, optionally together with excipients,can also be in the form of a lyophilizate and can be made into asolution before parenteral administration by the addition of suitablesolvents. Solutions such as are used, for example, for parenteraladministration can also be employed as infusion solutions. Themanufacture of injectable preparations is usually carried out understerile conditions, as is the filling, for example, into ampoules orvials, and the sealing of the containers.

The compounds of the disclosure may be administered as the sole activeingredient, or together with other drugs useful against neoplasticdiseases or useful in immunomodulating regimens. For example, thecompounds of the disclosure may be used in accordance with thedisclosure in combination with pharmaceutical compositions effective invarious diseases as described above, e.g. with cyclophosphamide,5-fluorouracil, fludarabine, gemcitabine, cisplatinum, carboplatin,vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel,rituxan, doxorubicine, gefitinib, or imatinib; or also withcyclosporins, rapamycins, ascomycins or their immunosuppressive analogs,e.g. cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus,corticosteroids, e.g. prednisone, cyclophosphamide, azathioprene,methotrexate, gold salts, sulfasalazine, antimalarials, brequinar,leflunomide, mizoribine, mycophenolic acid, mycophenolate, mofetil,15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g.monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4,CD7, CD25, CD28, I CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154,ICOS, LFA-1, VLA-4 or their ligands, or other immunomodulatorycompounds, e.g. CTLA41g.

The disclosure also provides for a pharmaceutical combinations, e.g. akit, comprising a) a first agent which is a compound of the disclosureas disclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

EXAMPLES

Various methods may be developed for synthesizing the at least onecompound of formula (I) and/or at least one pharmaceutically acceptablesalt thereof. Representative methods for synthesizing the at least onecompound of formula (I) and/or at least one pharmaceutically acceptablesalt thereof are provided in the Examples. It is noted, however, thatthe at least one compound of formula (I) and/or at least onepharmaceutically acceptable salt thereof may also be synthesized byother synthetic routes that others may devise.

It will be readily recognized that certain compounds of formula (I) haveatoms with linkages to other atoms that confer a particularstereochemistry to the compound (e.g., chiral centers). It is recognizedthat synthesis of the at least one compound of formula (I) and/or atleast one pharmaceutically acceptable salt thereof may result in thecreation of mixtures of different stereoisomers (enantiomers,diastereomers). Unless a particular stereochemistry is specified,recitation of a compound is intended to encompass all of the differentpossible stereoisomers.

The at least one compound of formula (I) can also be prepared as apharmaceutically acceptable acid addition salt by, for example, reactingthe free base form of the at least one compound with a pharmaceuticallyacceptable inorganic or organic acid. Alternatively, a pharmaceuticallyacceptable base addition salt of the at least one compound of formula(I) can be prepared by, for example, reacting the free acid form of theat least one compound with a pharmaceutically acceptable inorganic ororganic base. Inorganic and organic acids and bases suitable for thepreparation of the pharmaceutically acceptable salts of compounds offormula (I) are set forth in the definitions section of thisApplication. Alternatively, the salt forms of the compounds of formula(I) can be prepared using salts of the starting materials orintermediates.

The free acid or free base forms of the compounds of formula (I) can beprepared from the corresponding base addition salt or acid addition saltform. For example, a compound of formula (I) in an acid addition saltform can be converted to the corresponding free base thereof by treatingwith a suitable base (e.g., ammonium hydroxide solution, sodiumhydroxide, and the like). A compound of formula (I) in a base additionsalt form can be converted to the corresponding free acid thereof by,for example, treating with a suitable acid (e.g., hydrochloric acid,etc).

The N-oxides of the at least one compound of formula (I) and/or at leastone pharmaceutically acceptable salt thereof can be prepared by methodsknown to those of ordinary skill in the art. For example, N-oxides canbe prepared by treating an unoxidized form of the compound of formula(I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleicacid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, orthe like) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0 to 80° C.Alternatively, the N-oxides of the compounds of formula (I) can beprepared from the N-oxide of an appropriate starting material.

Compounds of formula (I) in an unoxidized form can be prepared fromN-oxides of compounds of formula (I) by, for example, treating with areducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine,lithium borohydride, sodium borohydride, phosphorus trichloride,tribromide, and the like) in an suitable inert organic solvent (e.g.,acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80° C.

Protected derivatives of the compounds of formula (I) can be made bymethods known to those of ordinary skill in the art. A detaileddescription of the techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, Protecting Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. For example, the following abbreviations may be used inthe examples and throughout the specification: g (grams); mg(milligrams); L (liters); mL (milliliters); μL (microliters); psi(pounds per square inch); M (molar); mM (millimolar); i.v.(intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol(millimoles); RT (room temperature); min (minutes); h (hours); mp(melting point); TLC (thin layer chromatography); Rt (retention time);RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA(triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroaceticanhydride); THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc(ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE(dichloroethane); DMF (N,N-dimethylformamide); DMPU(N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF(isobutyl chloroformate); HOAc (acetic acid); HOSu(N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et₂O (diethylether); EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride); BOC (tert-butyloxycarbonyl); FMOC(9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ(benzyloxycarbonyl); Ac (acetyl); atm (atmosphere); TMSE(2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS(triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP(4-dimethylaminopyridine); Me (methyl); OMe (methoxy); Et (ethyl); tBu(tert-butyl); HPLC (high pressure liquid chomatography); BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF(tetra-n-butylammonium fluoride); m-CPBA (meta-chloroperbenzoic acid).

References to ether or Et₂O are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionswere conducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Varian Mercury Plus 400. Chemicalshifts are expressed in parts per million (ppm). Coupling constants arein units of hertz (Hz). Splitting patterns describe apparentmultiplicities and are designated as s (singlet), d (doublet), t(triplet), q (quartet), m (multiplet), and br (broad).

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Shimadzu LC/MS single quadrapole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E. Merck silica gel plates (60F-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, ninhydrin, orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

Synthetic Schemes

Synthetic methods for preparing the compounds of the present inventionare illustrated in the following Schemes and Examples. Startingmaterials are commercially available or may be made according toprocedures known in the art or as illustrated herein.

The compounds of formula I-a in the present invention can be preparedfrom intermediates such as those of formula II-h, wherein LG is aleaving group such as halogen or OTf that can be substituted with anappropriate amine under the reacting conditions known in the art to givethe corresponding compounds of formula I-a.

The preparation of these intermediates is described in the followingSchemes, wherein X is a halogen such as Cl or F. Compounds of formula Hamay be prepared as illustrated in Scheme 1. Pyridazinone II-b wasprepared using method described in Douglas E. Murphy et al., TetrahedronLett., 2008, 49, 811. Reaction of pyridazinone II-b with chlorinatingagent such as oxalyl chloride followed by the substitution of theresulting chloride with alkyl amine provides amine II-d. Acylation ofII-d with a properly substituted ethyl malonyl chloride in a polarsolvent such as acetonitrile leads to II-e. Dieckmann condensation ofII-e in the presence of a base such as NaOEt gives beta ketone esterII-f. Treatment of II-f with a halogenating agent followed bydecarboxylation under such a condition as 2N H₂SO₄ provides intermediateII-a.

Compounds of formula I-a may be prepared from II-h as illustrated inScheme 2. Sulfonylation of intermediate II-a with such an agent assulfonyl anhydride or sulfonyl chloride provide sulfonate ester II-h.Substitution of the resulting sulfonate ester with amine in a solventsuch as toluene provides I-a.

Further modification may be needed depending on the functionalities onthe substituents such as R² and R³.

One such case is illustrated in scheme 3. Reduction of the nitro groupin I-aa with a reducing reagent such as SnCl₂ provide aniline I-ab,reaction of aniline I-ab with acyl chloride lead to amide I-ac,dihydroxylation of allyl group in I-ac give diol I-ad.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

Preparation of the Intermediates Intermediate A2-(3-nitrophenyl)-2-oxoacetic acid (A-1)

To a solution of 2-oxo-2-phenylacetic acid (50.0 g, 0.33 mol) in H₂SO₄(400 mL) was added KNO₃ (40.4 g, 0.4 mol) at 0° C. The mixture waswarmed to ambient temperature and stirred at 25° C. for 3 h. Thereaction mixture was poured into ice-water (1.6 L) and extracted withEtOAc (2×300 mL). The organic extracts were combined and washed withwater, brine and dried over anhydrous sodium sulfate and concentrated invacuo to give the title compound A-1 as crude product (63.1 g, 97%).

Methyl 2-(3-nitrophenyl)-2-oxoacetate (A-2)

To a solution of 2-(3-nitrophenyl)-2-oxoacetic acid (A-1) (60.0 g, 30.8mmol) in DMF (700 mL) was added K₂CO₃ (112 g, 81.2 mmol). After stirringat ambient temperature for 2 h, iodomethane (100 mL, 150.4 mmol) wasadded dropwise. After being stirred overnight at ambient temperature,the mixture was diluted with EtOAc and washed with water. The organicextracts were washed with brine, dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. Flash chromatography (PE:ethylacetate=10:1) of the residue gave the title compound A-2 (44 g, 68%).

Ethyl 3-hydrazinyl-3-oxopropanoate (A-3)

This reagent was prepared according to the method described inliterature: E. J. Med. Chem. 2008, 43: 584.

Ethyl3-(2-(2-ethoxy-1-(3-nitrophenyl)-2-oxoethylidene)hydrazinyl)-3-oxopropanoate(A-4)

To a solution of methyl 2-(3-nitrophenyl)-2-oxoacetate (A-2) (10.0 g,47.9 mmol) and ethyl 3-hydrazinyl-3-oxopropanoate (A-3) (7.00 g, 47.9mmol) in EtOH (100 mL) was added H₂SO₄ (0.6 mL) at ambient temperature.The mixture was heated at reflux for 2 h. The solution was concentratedand extracted with EtOAc. The organic extracts were washed with water,brine, and dried over anhydrous sodium sulfate. The solid was filteredand the solution was concentrated in vacuo to give the title compoundA-4 (14.7 g, E/Z mixture), which was used in the next step withoutfurther purification. MS-ESI (m/z): 352 [M+1]⁺.

Ethyl5-hydroxy-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(A-5)

To a solution of ethyl 3-(2-(2-ethoxy-1-(3-nitrophenyl)-2-oxoethylidene)hydrazinyl)-3-oxopropanoate (A-4) (14.7 g, 43.6 mmol) in DMF (80 mL) wasadded K₂CO₃ (3.60 g, 26.2 mmol). After being stirred at 80° C. for 3 h,the mixture was cooled to ambient temperature and poured into 3 N HCl(300 mL). The precipitated solid was collected by filtration to give theA-5 (13.4 g, two steps 91%). MS-ESI (m/z): 306 [M+1]⁺.

Ethyl5-hydroxy-2-methyl-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(A-6)

To a solution of ethyl5-hydroxy-6-(3-nitrophenyl)-3-oxo-2,3dihydropyridazine-4-carboxylate(A-5) (8.00 g, 26.1 mmol) in DMF (150 mL) was added NaH (2.10 g, 52.2mmol). After being stirred at ambient temperature for 30 min, thesolution was cooled to −10° C., iodomethane (1.70 mL, 27.4 mmol) wasadded dropwise over 10 min. The reaction temperature was slowly warmedup to 10° C. After being stirred at the same temperature for 1 h, themixture was acidified with 1 N HCl (20 mL) and extracted with EtOAc (300mL). The organic extracts were washed with water and brine, dried overanhydrous sodium sulfate, and then concentrated in vacuo to give A-6(8.80 g, 99%) as yellow solid. MS-ESI (m/z): 320 [M+1]⁺.

Ethyl5-chloro-2-methyl-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(A-7)

To a solution of ethyl5-hydroxy-2-methyl-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(A-6) (8.80 g, 27.5 mmol) in DCM (150 mL) was added oxalyl chloride(23.6 mL, 27.5 mmol) and DMF (10 μL). The mixture was stirred at 30-40°C. for 4 h. The solution was concentrated in vacuo to give the titlecompound A-7 (9.50 g, 100%), MS-ESI (m/z): 338 [M+1]⁺.

Ethyl2-methyl-5-(Methylamino)-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(A-8)

To a solution of ethyl5-chloro-2-methyl-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(A-7) (9.50 g, 27.5 mmol) in DCM (100 mL) at 0° C. was added 50 mL ofMeNH₂/EtOH (25-30%) dropwise. After being stirred at 0° C. to ambienttemperature for 1 h, the mixture was concentrated and extracted withEtOAc (200 mL). The organic extracts were washed with water and brine,dried over anhydrous sodium sulfate, and then concentrated in vacuo togive the title compound A-8 (9.20 g), which was used in next stepwithout further purification. MS-ESI (m/z): 333 [M+1]⁺.

Ethyl5-(3-ethoxy-N-methyl-3-oxopropanamido)-2-methyl-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(A-9)

To a solution of ethyl2-methyl-5-(methylamino)-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(A-8) (9.0 g, 27 mmol) in CH₃CN (120 mL) was added ethyl3-chloro-3-oxopropanoate (11 mL). Then the mixture was heated to 80° C.for 2 h. The mixture was concentrated in vacuo. Flash chromatography(PE:ethyl acetate=4:1, then DCM:MeOH=10:1) of the residue gave the titlecompound A-9 (9.4 g). MS-ESI (m/z): 447 [M+1]⁺.

Ethyl1,6-dimethyl-8-(3-nitrophenyl)-2,4,5-trioxo-1,2,3,4,5,6-hexahydropyrido[3,2-d]pyridazine-3-carboxylate(A-10)

To a solution of ethyl5-(3-ethoxy-N-methyl-3-oxopropanamido)-2-methyl-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(A-9) (9.4 g, 21 mmol) in MeOH (100 mL) was added MeONa (2.3 g, 43 mmol)at 0° C. and the mixture was stirred at the same temperature for 1 h.The mixture was concentrated in vacuo, the residue was acidified with 1N HCl to pH 4-5 and extracted with EtOAc (300 mL). The organic extractswere washed with water and brine, dried over anhydrous sodium sulfate,and then concentrated in vacuo to give the title compound A-10 (6.9 g,82%). MS-ESI (m/z): 401[M+1]⁺.

Ethyl3-fluoro-1,6-dimethyl-8-(3-nitrophenyl)-2,4,5-trioxo-1,2,3,4,5,6-hexahydropyrido[3,2-d]pyridazine-3-carboxylate(A-11)

To a solution of ethyl1,6-dimethyl-8-(3-nitrophenyl)-2,4,5-trioxo-1,2,3,4,5,6-hexahydropyrido[3,2-d]pyridazine-3-carboxylate(A-10) (4.0 g, 10 mmol) and sodium acetate (1.64 g, 20 mmol) inanhydrous CH₃CN (350 mL) was added Select-Fluor (3.72 g, 10.5 mmol) at0° C. After being stirred at 0° C. for 3 h, the mixture was concentratedin vacuo. The residue was purified by chromatography on silica gel,eluting with 25% DCM in PE and then with 25% THF in DCM to give thetitle compound A-11 (4.18 g). MS-ESI (m/z): 419 [M+1]⁺.

3-Fluoro-4-hydroxy-1,6-dimethyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(Intermediate A)

To a solution of crude ethyl3-fluoro-1,6-dimethyl-8-(3-nitrophenyl)-2,4,5-trioxo-1,2,3,4,5,6-hexahydropyrido[3,2-d]pyridazine-3-carboxylateA-11 (5.3 g) in THF (200 mL) was added 2 N H₂SO₄ (200 mL) at roomtemperature. After being stirred at 90° C. for 5 h, the solution wascooled to room temperature, concentrated in vacuo, and extracted withDCM. The organic extracts were washed with water and brine, dried overanhydrous sodium sulfate, and then concentrated in vacuo to give thetitle compound Intermediate A (4.7 g). MS-ESI (m/z): 347.0 [M+1]⁺.

Intermediates B-H listed in Table 1 were prepared following essentiallythe same procedures as described for the intermediate A by substitutingmethyl iodide with corresponding alkyl halide listed in the table.

TABLE 1 RX Intermediate Data

B MS-ESI (m/z): 361.0 [M + 1]⁺

C MS-ESI (m/z): 375.0 [M + 1]⁺

D MS-ESI (m/z): 373.0 [M + 1]⁺

E MS-ESI (m/z): 375.0 [M + 1]⁺

F MS-ESI (m/z): 379.0 [M + 1]⁺

G MS-ESI (m/z): 397.0 [M + 1]⁺

H MS-ESI (m/z): 391.0 [M + 1]⁺

Intermediate I Ethyl5-chloro-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(I-1)

To a solution of ethyl5-hydroxy-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(A-5) (9.40 g, 30.7 mmol) in DCM (60 mL) was added oxalyl chloride (26mL, 307.2 mmol) at ambient temperature, followed by addition of 3 dropsof DMF. After being stirred at 35° C. for 3 h, the reaction mixture wasconcentrated in vacuo. The residue was dissolved in DCM, washed withwater and brine, dried over anhydrous sodium sulfate, and thenconcentrated in vacuo to give I-1 (9.1 g), which was used in the nextstep without further purification. MS-ESI (m/z): 324.0 [M+1]⁺.

Ethyl5-chloro-2-cyclopropyl-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(I-2)

To a suspension of ethyl5-chloro-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(I-1) (9.10 g, 28.1 mmol), cyclopropyl boronic acid (4.83 g, 56.2 mmol),2,2′-bipyridine (5.26 g, 70.2 mmol), sodium carbonate (7.44 g, 33.7mmol) in anhydrous 1,2-dichloroethane (100 mL) was added diacetoxycopper(6.74 g, 33.7 mmol) under N₂ atmosphere at ambient temperature. Afterbeing stirred at 70° C. for 2 days, the mixture was diluted with DCM andwashed with water and brine. The organic extracts were washed withbrine, dried over anhydrous sodiumsulfate, and then concentrated invacuo. Flash chromatography (silica, hexane:ethyl acetate=3:1) of theresidue gave the title compound I-2, (1.94 g). MS-ESI (m/z): 364.0[M+1]⁺.

Ethyl2-cyclopropyl-5-(Methylamino)-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(I-3)

To a solution of ethyl5-chloro-2-cyclopropyl-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(I-2) (1.9 g) in DCM (18 mL) was added a solution of MeNH₂ (10 mL,27-32%) at 0° C. After being stirred at ambient temperature for 1.5 h,the reaction mixture was concentrated. The residue was dissolved in DCM,washed with water and brine, dried over Na₂SO₄ and concentrated to givethe crude title compound I-3 (1.53 g), which was used in the next stepwithout further purification. MS-ESI (m/z): 359.0 [M+1]⁺.

6-Cyclopropyl-3-fluoro-4-hydroxy-1-methyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(Intermediate I)

Intermediate I was prepared following the same procedure as describedfor intermediate A by substituting A-8 with I-3.

Intermediate J Ethyl2-allyl-5-(methylamino)-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(J-1)

Intermediate J-1 was prepared following essentially the same procedureas described for Intermediate A by substituting methyl iodide with allylbromide.

Ethyl2-allyl-5-(2-chloro-N-methylacetamido)-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(J-2)

A solution of2-allyl-5-(methylamino)-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(J-1) (1.20 g, 3.35 mmol) in chloroacetyl chloride (20 mL) was heated toreflux for 2 h. Then the excess of chloroacetyl chloride was removed invacuo. The residue was purified by column chromatography on silica gel,eluting with PE/acetone (6:1-4:1) to give the title compound J-2 (0.63g). MS-ESI (m/z): 435[M+1]⁺.

6-Allyl-3-chloro-1-methyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,4,5(1H,3H,6H)-trione(Intermediate J)

To a solution of ethyl2-allyl-5-(2-chloro-N-methylacetamido)-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate(J-2) (0.59 g, 1.36 mmol) in EtOH (20 mL) was added EtONa (92 mg, 1.36mmol). The reaction mixture was diluted with EtOAc and water, 1 N HClwas added until pH=1-2. The organic phase was washed with water andbrine, dried over MgSO₄ and concentrated. The residual was purified bycolumn chromatography on silica gel, eluting with DCM/MeOH=100:1 to givethe title compound Intermediate J (0.40 g). MS-ESI (m/z): 389 [M+1]⁺.

Example 16-Cyclopropyl-3-fluoro-1-methyl-8-(3-nitrophenyl)-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-4-yltrifluoromethanesulfonate (1a)

To a solution of6-cyclopropyl-3-fluoro-4-hydroxy-1-methyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(Intermediate I) (1.44 g, 3.86 mmol) in anhydrous CH₃CN (55 mL) at 0° C.was added DIPEA (2.70 mL, 7.54 mmol) and 20 μL of NMP. After beingstirred at 0° C. for 10 min, trifluoromethanesulfonic anhydride (1.06 g,3.75 mmol) was added dropwise over 30 min. After being stirred at 0° C.to ambient temperature for 1 h, another portion oftrifluoromethanesulfonic anhydride (1.06 g, 3.75 mmol) was addeddropwise. The reaction system was purified by silica gel column, elutingwith PE, DCM, 10% THF in DCM, to give the title compound 1a (1.84 g).MS-ESI (m/z): 505.0 [M+1]⁺.

6-Cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(1b)

A mixture of6-cyclopropyl-3-fluoro-1-methyl-8-(3-nitrophenyl)-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-4-yltrifluoromethanesulfonate (1a) (1.84 g, 3.64 mmol),2-fluoro-4-iodoaniline (18.0 g, 75.6 mmol) and toluene (4 mL) was heatedat 105° C. for 1.5 h. The residue was purified by chromatography onsilica gel, eluting with PE, DCM, THF/DCM (1:100) to give product of 1b(720 mg). MS-ESI (m/z): 592.0 [M+1]⁺.

8-(3-Aminophenyl)-6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(1c)

To a solution of6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione1b (720 mg, 1.22 mmol) in THF (20 mL) and ethanol (20 mL) was addedstannous chloride hydrate (1.40 g, 6.08 mmol) at ambient temperature.The mixture was refluxed for 1.5 h. After cooling to ambienttemperature, the mixture was quenched with 30% aqueous ammonia. Thesolid was removed by filtration. The filtrate was extracted with DCM.The extracts were washed with 30% aqueous ammonia, water, and brine,dried over Na₂SO₄ and concentrated to give the title compound 1c, whichwas used in next step without further purification. MS-ESI (m/z): 562.0[M+1]⁺.

N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide(1)

To a solution of6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(1c) (47 mg, 0.084 mmol) and TEA (300 μL, 2.1 mmol) in DCM (1 mL) wasadded acetyl chloride (30 μL, 0.335 mmol) at 0° C. After being stirredat ambient temperature for 1.5 h, the mixture was diluted with DCM,washed with water and brine, dried over Na₂SO₄, and concentrated. Theresidue was purified by column chromatography on silica gel, elutingwith DCM/MeOH (66:1) to give the title compound 1 (16 mg). MS-ESI (m/z):604 [M+1]⁺.

Example 2N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propionamide(2)

The title compound 2 was prepared following the same procedure asdescribed for Example 1 by substituting acetyl chloride with propionylchloride. MS-ESI (m/z): 618.0 [M+1]⁺.

Example 3N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)isobutyramide(3)

The title compound 3 was prepared following the same procedure asdescribed for Example 1 by substituting acetyl chloride with isobutyrylchloride. MS-ESI (m/z): 632 [M+1]⁺.

Example 4 N-(3-(6-cyclopropyl-3fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanecarboxamide(4)

The title compound 4 was prepared following the same procedure asdescribed for Example 1 by substituting acetyl chloride withcyclopropanecarbonyl chloride. MS-ESI (m/z):630 [M+1]⁺.

Example 5N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide(5)

To a solution of6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione1c (47 mg, 0.084 mmol) in pyridine (2 mL) was added methanesulfonylchloride (19 μl, 0.25 mmol) at 0° C. After being stirred at 0° C.-roomtemperature for 3 h, the mixture was diluted with DCM. The solution waswashed with 1 N HCl, water and brine, dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel to give title compound 5 (17.2 mg). MS-ESI (m/z): 640.0[M+1]⁺.

Example 6N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)ethanesulfonamide(6)

The title compound 6 was prepared following the same procedure asdescribed for Example 5 by substituting methanesulfonyl chloride withethanesulfonyl chloride. MS-ESI (m/z): 654.0 [M+1]⁺.

Example 7N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide(7)

The title compound 7 was prepared following the same procedure asdescribed for Example 5 by substituting methanesulfonyl chloride withpropane-2-sulfonyl chloride. MS-ESI (m/z): 668 [M+1]⁺.

Example 8N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide(8)

The title compound 8 was prepared following the same procedure asdescribed for Example 5 by substituting methanesulfonyl chloride withcyclopropanesulfonyl chloride. MS-ESI (m/z): 666 [M+1]⁺.

Following essentially the same procedures outlined for Examples 1-8, thecompounds of Examples 9-34 listed in Table 2 were prepared from thecorresponding intermediates listed in Table 1. The name and structure ofExamples 9-34 are given below.

TABLE 2 EXAMPLE NAME DATA 9N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1- MS-ESI(m/z): methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 606[M + 1]⁺ 8-yl)phenyl)acetamide 10N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1- MS-ESI(m/z): methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 620[M + 1]⁺ 8-yl)phenyl)propionamide 11N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1- MS-ESI(m/z): methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 634[M + 1]⁺ 8-yl)phenyl)isobutyramide 12N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1- MS-ESI(m/z): methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 632[M + 1]⁺ 8-yl)phenyl)cyclopropanecarboxamide 13N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1- MS-ESI(m/z): methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 642[M + 1]⁺ 8-yl)phenyl)methanesulfonamide 14N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1- MS-ESI(m/z): methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 656[M + 1]⁺ 8-yl)phenyl)ethanesulfonamide 15N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1- MS-ESI(m/z): methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 670[M + 1]⁺ 8-yl)phenyl)propane-2-sulfonamide 16N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1- MS-ESI(m/z): methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 668[M + 1]⁺ 8-yl)phenyl)cyclopropanesulfonamide 17N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5- MS-ESI(m/z): dioxo-6-propyl-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 668.0[M + H]⁺ 8-yl)phenyl)cyclopropanesulfonamide 18N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-(2-methoxyethyl)-1-MS-ESI (m/z): methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-684 [M + 1]⁺ 8-yl)phenyl)cyclopropanesulfonamide 19N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-(2-fluoroethyl)-1-MS-ESI (m/z): methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-672 [M + 1]⁺ 8-yl)phenyl)cyclopropanesulfonamide 20N-(3-(6-(2,2-difluoroethyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-MS-ESI (m/z): methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-690 [M + 1]⁺ 8-yl)phenyl)cyclopropanesulfonamide 21N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1,6-dimethyl- MS-ESI(m/z): 2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8- 578 [M +1]⁺ yl)phenyl)acetamide 22N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1,6-dimethyl- MS-ESI(m/z): 2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8- 614 [M +1]⁺ yl)phenyl)methanesulfonamide 23N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1,6-dimethyl- MS-ESI(m/z): 2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8- 640 [M +1]⁺ yl)phenyl)cyclopropanesulfonamide 24N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 592 [M + 1]⁺8-yl)phenyl)acetamide 25N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 628 [M + 1]⁺8-yl)phenyl)methanesulfonamide 26N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 656 [M + 1]⁺8-yl)phenyl)propane-2-sulfonamide 27N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 654 [M + 1]⁺8-yl)phenyl)cyclopropanesulfonamide 28N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 604 [M + 1]⁺8-yl)phenyl)acetamide 29N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 618 [M + 1]⁺8-yl)phenyl)propionamide 30N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 630 [M + 1]⁺8-yl)phenyl)cyclopropanecarboxamide 31N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 640 [M + 1]⁺8-yl)phenyl)methanesulfonamide 32N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 654 [M + 1]⁺8-yl)phenyl)ethanesulfonamide 33N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 668 [M + 1]⁺8-yl)phenyl)propane-2-sulfonamide 34N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 666 [M + 1]⁺8-yl)phenyl)cyclopropanesulfonamide 35N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1- MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin- 632 [M + 1]⁺8-yl)phenyl)isobutyramide

Example 36N-(3-(6-allyl-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide(36)

The title compound 36 was prepared following the same procedure asdescribed for Example 1 by substituting Intermediate I with IntermediateD and 2-fluoro-4-iodoaniline with 4-bromo-2-fluoroaniline.

Example 37N-(3-(6-allyl-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide(37)

The title compound 37 was prepared following the same procedure asdescribed for Example 1 and Example 5 by substituting intermediate Iwith intermediate D and 2-fluoro-4-iodoaniline with4-bromo-2-fluoroaniline.

Example 38N-(3-(6-allyl-3-chloro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide(38)6-Allyl-3-chloro-1-methyl-8-(3-nitrophenyl)-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-4-yl4-methylbenzenesulfonate (38a)

To a solution of6-allyl-3-chloro-1-methyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,4,5(1H,3H,6H)-trione(Intermediate J, 0.100 g, 0.258 mmol) in DCM (5 mL) at ambienttemperature was added TsCl (148 mg, 0.774 mmol), TEA (78 mg, 0.774 mmol)and catalytic amount of DMAP. After being stirred at ambient temperaturefor 1.5 h, the mixture was concentrated and purified by columnchromatography on silica gel, eluting with PE: EtOAc=5:1 then to 2:1 togive the title compound 38a (20 mg). MS-ESI (m/z): 543 [M+1]⁺.

6-allyl-3-chloro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H]-dione(38b)

To a solution of6-allyl-3-chloro-1-methyl-8-(3-nitrophenyl)-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-4-yl4-methylbenzenesulfonate 38a (20 mg, 0.037 mmol) and2-fluoro-4-iodoaniline (8.77 mg, 0.0377 mmol) in THF (1 mL) at ambienttemperature was added 60% NaH (20 mg). After being stirred at rt for 1h, the reaction mixture was quenched with water and extracted with DCM.The extracts were washed with water and brine, dried over Na₂SO₄ andconcentrated to give the title compound 38b (9 mg). MS-ESI (m/z): 608[M+1]⁺.

6-Allyl-8-(3-aminophenyl)-3-chloro-4-((2-fluoro-4-iodophenyl)amino)-1-methylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(38c)

To a solution of6-allyl-3-chloro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-8-(3-nitrophenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione38b (9 mg, 0.0148 mmol) in THF/EtOH (6 mL, v/v=1:1) was added SnCl₂.2H₂O (17 mg). After being stirred at 70° C. for 2 h, the mixture wasdiluted with DCM/i-PrOH (v/v=4:1). The solution was washed with ammoniumhydroxide, water and brine, dried over Na₂SO₄ and concentrated to givethe title compound 38c, which was used directly in next step withoutfurther purification. MS-ESI (m/z): 577 [M+1]⁺

N-(3-(6-allyl-3-chloro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide(38)

To a solution of the crude product 38c from Step C in THF (0.5 mL) wasadded TEA (20 μL) and acetyl chloride (15 μL). The reaction mixture wasstirred at ambient temperature for 1 h, diluted with water and extractedwith DCM. The extract was washed with water and brine, dried over Na₂SO₄and concentrated. The residue was purified by preparative TLC to givethe title compound 38 (4.5 mg). MS-ESI (m/z): 620 [M+1]⁺ _(.)

Example 39N-(3-(3-chloro-6-(2,3-dihydroxypropyl)-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazine-8-yl)phenyl)acetamide(39)

To a solution ofN-(3-(6-allyl-3-chloro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide38 (2.7 mg) in THF/water (1 mL, v/v=1:1) was added NMO (cat.) followedby OsO₄ in toluene (20 mg/mL, 0.1 mL). After being stirred at rt for 12h, the mixture was quenched with saturated aq. Na₂SO₃ and extracted withDCM. The extract was washed with water and brine, dried over Na₂SO₄ andconcentrated to give the title compound 39 (2.6 mg). MS-ESI (m/z): 654[M+1]⁺.

Following essentially the same procedures outlined for Examples 39, thecompounds of Examples 39-46 listed in Table 3 were prepared from thecompounds of Examples 28-34 listed in Table 2 respectively. The namesand structures of the compounds of Examples 40-46 are given below.

TABLE 3 EXAMPLE NAME DATA 40N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8- 638 [M +1]⁺ yl)phenyl)acetamide 41N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8- 652 [M +1]⁺ yl)phenyl)propionamide 42N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8- 664 [M +1]⁺ yl)phenyl)cyclopropanecarboxamide 43N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8- 674 [M +1]⁺ yl)phenyl)methanesulfonamide 44N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8- 688 [M +1]⁺ yl)phenyl)ethanesulfonamide 45N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8- 702 [M +1]⁺ yl)phenyl)propane-2-sulfonamide 46N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-MS-ESI (m/z):methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8- 700 [M +1]⁺ yl)phenyl)propane-2-sulfonamide

Example 47N-(3-(6-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylmethanesulfonamide(47)

To a solution ofN-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide(5) (100 mg, 0.156 mmol) and K₂CO₃ in DMF (10 mL) was added methyliodide (22 mg, 0.156 mmol) dropwise at room temperature. After beingstirred at room temperature for 1 h, the reaction mixture was extractedwith EtOAc. The extracts were washed with water and brine, dried overNa₂SO₄ and concentrated to give the title compound 47 (54 mg) as yellowsolid. MS-ESI (m/z): 654 [M+1]⁺.

Example 48N-(3-(6-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylpropane-2-sulfonamide(48)

The title compound 48 was prepared following the same procedure asdescribed for Example 47 by substituting compound 5 with compound 7.MS-ESI (m/z): 682 [M+1]⁺.

Example 49N-(3-(6-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazine-8-yl)phenyl)-N-methylcyclopropanesulfonamide(49)

The title compound 49 was prepared following the same procedure asdescribed for Example 47 by substituting compound 5 with compound 8.MS-ESI (m/z): 680 [M+1]⁺.

Example 50N-(3-(3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylmethanesulfonamide(50)

The title compound 50 was prepared following the same procedure asdescribed for Example 47 by substituting compound 5 with compound 22.MS-ESI (m/z): 628 [M+1]⁺.

Example 51N-(3-(3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide(51a)

Following essentially the same procedures outlined for Examples 7, thetitled compound 51a were prepared from intermediates A. MS-ESI (m/z):642 [M+1]⁺.

N-(3-(3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylpropane-2-sulfonamide(51)

The title compound 51 was prepared following the same procedure asdescribed for Example 47 by substituting compound 5 with compound 51a.MS-ESI (m/z): 656 [M+1]⁺.

Example 52N-(3-(3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazine-8-yl)phenyl)-N-methylcyclopropanesulfonamide(52)

The title compound 52 was prepared following the same procedure asdescribed for Example 47 by substituting compound 5 with compound 23.MS-ESI (m/z): 654 [M+1]⁺.

Example 536-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-8-(3-(2-oxopyrrolidin-1-yl)phenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(53)

To a solution of8-(3-Aminophenyl)-6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(1c) (84 mg, 0.15 mmol) and triethylamine (64 mg, 0.60 mmol) indichloromethane (10 mL) was added 4-chlorobutanoyl chloride (63 mg, 0.45mmol) dropwise at room temperature. After being stirred at roomtemperature for 1 h, the reaction mixture was extracted with DCM. Theextracts were washed with water and brine, dried over Na₂SO₄ andconcentrated. The residue was dissolved in DMF (5 mL) followed byaddition of DBU (45.6 mg, 0.30 mmol). The reaction mixture was stirredat room temperature for 1 h and was extracted with EtOAc. The extractswere washed with water and brine, dried over Na₂SO₄ and concentrated togive the title compound 53 (45 mg) as yellow solid. MS-ESI (m/z): 630[M+1]⁺.

Example 548-(3-aminophenyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1,6-dimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(54a)

The title compound 54a was prepared following the same procedure asdescribed for Compound 1c by substituting Intermediate I withIntermediate A. MS-ESI (m/z): 535 [M+1]⁺.

3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-8-(3-(2-oxopyrrolidin-1-yl)phenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(54)

The title compound 54 was prepared following the same procedure asdescribed for Example 53 by substituting compound 1c with compound 54a.MS-ESI (m/z): 604 [M+1]⁺.

Example 556-cyclopropyl-8-(3-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(55)

To a solution of8-(3-Aminophenyl)-6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(1c) (84 mg, 0.15 mmol) in pyridine (2 mL) was added3-chloropropane-1-sulfonyl chloride (80 mg, 0.45 mmol) dropwise at roomtemperature. After being stirred at room temperature for 1 h, thereaction mixture was extracted with DCM. The extracts were washed withwater and brine, dried over Na₂SO₄ and concentrated. The residue wasdissolved in DMF (5 mL) followed by addition of DBU (45.6 mg, 0.30mmol). The reaction mixture was stirred at room temperature for 1 h andwas extracted with EtOAc. The extracts were washed with water and brine,dried over Na₂SO₄ and concentrated to give the title compound 55 (55 mg)as yellow solid. MS-ESI (m/z): 666 [M+1]⁺.

Example 568-(3-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(56)

The title compound 56 was prepared following the same procedure asdescribed for Example 55 by substituting compound 1c with compound 54a.MS-ESI (m/z): 640 [M+1]⁺.

Reference Compound4-((2-fluoro-4-methylphenyl)amino)-1,3,8-trimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(57)(Example 165 of U.S. Pat. No. 7,517,994) Ethyl4,4-dicyano-2-methyl-3-oxobutanoate (57a)

To a solution of malononitrile (76 g, 1.18 mol) and diethylmethylmalonate (200 g, 1.15 mol) in THF (1200 ml) was added DBU (350 g,2.3 mol) at −50° C., and the mixture was warmed to RT and stirredovernight. The mixture was diluted with EA (4000 ml), washed with 2 NHCl (2000 ml) and brine (2000 ml), dried over Na₂SO₄, and concentratedto dryness. The residue was purified by column chromatography to givethe title compound 57a (15 g).

2-amino-4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(57b)

A mixture of ethyl 4,4-dicyano-2-methyl-3-oxobutanoate (57a) (9 g, 46.4mmol) and methylamine (30% methanol solution, 150 ml, 1.45 mol) wasstirred at RT for 40 h. The reaction mixture was concentrated in vacuoand diluted with methanol (150 ml). The solution was added sodiummethanolate (7.5 g, 139 mmol) and stirred at 55° C. for 2 h, then cooledto 0˜5° C. The pH of the mixture was adjusted to 2˜3 by addition of HCl(12 N). The resulting mixture was concentrated in vacuo, the residue wasdiluted with THF and filtrated, the filtrate was concentrated andpurified by column chromatography to give the title compound 57b (2.2g). MS-ESI (m/z): 180 [M+1]⁺.

2-Amino-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(57c)

To a solution of2-amino-4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(57b) (2.1 g, 11.7 mmol) in MeCN (40 ml) was added oxalyl dichloride(10.5 ml, 122.4 mmol) dropwise at 5° C., and the mixture was stirred atRT for 1 h. The reaction mixture was concentrated in vacuo to give thetitle compound 57c (2.6 g). MS-ESI (m/z): 198 [M+1]⁺.

2-bromo-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(57d)

To a suspension of CuBr (1.6 g, 11.2 mmol) and2-amino-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(57c) (2.6 g, 11.7 mmol) in MeCN (80 ml) was added t-butyl nitrite (2 g,19.4 mmol), and the mixture was stirred at RT for 3 h. The reactionmixture was concentrated and purified by column chromatography to givethe title compound 57d (1.6 g).

4-chloro-2-(1-ethoxyvinyl)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(57e)

A mixture of2-bromo-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(57d) (200 mg, 0.76 mmol), tributyl(1-ethoxyvinyl)stannane (820 mg, 2.27mmol) and bis(triphenylphosphine)palladium(II) chloride (120 mg, 0.17mmol) in THF (20 ml) was stirred under nitrogen at 70° C. for 14 h. Thereaction mixture was quenched with aqueous KF solution (10%, 10 ml) andextracted with EA (20 ml). The organic layer was washed with brine,dried over Na₂SO₄, and purified by preparative thin layer chromatographyto give the title compound 57e (70 mg). MS-ESI (m/z): 253 [M+1]⁺.

2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(57f)

To a solution of4-chloro-2-(1-ethoxyvinyl)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(57e) (70 mg, 0.28 mmol) in MeCN (6 ml) was added hydrochloric acid(36%, 3 ml, 36 mmol), and the mixture was stirred at RT for 5 h. Thereaction mixture was quenched with brine and extracted with EA, theorganic layer was dried over Na₂SO₄ and purified by preparative thinlayer chromatography to give the title compound 57f (24 mg). MS-ESI(m/z): 225 [M+1]⁺.

4-chloro-1,3,8-trimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione (57g)

To a solution of2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbonitrile(57f) (2 mg, 8.9 μmol) and acetic acid (8 mg, 133 μmol) in 1,4-dioxane(0.5 ml) was added hydrazine hydrate (8 mg, 160 μmol), and the mixturewas stirred at 70° C. for 44 h. The reaction mixture was concentrated invacuo, the residue was diluted with EA, washed with water and brine,dried over Na₂SO₄ and purified by preparative thin layer chromatographyto give the title compound 57f (0.8 mg). MS-ESI (m/z): 240 [M+1]⁺.

4-((2-fluoro-4-methylphenyl)amino)-1,3,8-trimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione(57)

To a solution of 2-fluoro-4-methylaniline (1.3 mg, 10.4 μmol) and4-chloro-1,3,8-trimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione (57g)(2.3 mg, 9.6 μmol) in THF (0.5 ml) was added lithiumbis(trimethylsilyl)amide (1 M, 0.7 ml, 0.7 mmol) dropwise at −70° C.,and the mixture was warmed to RT naturally, quenched with saturatedaqueous ammonium chloride solution and extracted with EA. The EA layerwas dried over Na₂SO₄ and purified by preparative thin layerchromatography to give the title compound 57 (1.5 mg). MS-ESI (m/z): 329[M+1]⁺.

Biological Activity

Materials and Preparation of Reagents

MTS testing kit was purchased from Promega. The DMEM, RPMI-1640 andFetal bovine serum were purchased from Gibco. Dimethyl sulfoxide (DMSO)was purchased from Sigma.

Inhibition Activity of Cell Proliferation

To investigate whether a compound is able to inhibit the activity of MEKin cells, a mechanism-based assay using A-375 and HT-29 cell wasdeveloped. In this assay, inhibition of MEK was detected by theinhibition of A-375 and HT-29 cells proliferation. A-375 and HT-29 cellswere cultured in culture flasks to 40-80% confluence respectively inDMEM and RPMI-1640 plus 10% fetal bovine serum. Cells were collected andplated onto 96-well plates at desired cell density (A-375: 3000cells/well; HT-29: 5000 cells/well). Plates were incubated overnight at37° C., with 5% CO₂ to adhere. Compounds were added to the plates. Thefinal compound concentrations were 1000, 333.3, 111.1, 27.04, 12.35,4.12, 1.37, 0.46 and 0.15 nM, respectively. Place plates at 37° C., with5% CO₂ for 72 h. 10 μl MTS were added to each well and incubate theplates for exactly 2 hours. Absorbance was measured at 490 nm. IC₅₀ wascalculated using GraphPad Prism 5.0.

Biological Data for Select Compounds

Select compounds prepared as described above were assayed according tothe biological procedures described herein. The results are given inTable 4:

TABLE 4 A375 HT29 Example IC₅₀ (nM) IC₅₀ (nM) 1 1.2 2.4 2 10.6 13.7 315.3 41.4 4 26.6 41.9 5 4.0 5.1 6 4.8 6.4 7 3.5 4.1 8 5.4 5.4 9 44.047.3 10 61.2 59.6 11 198.3 180.3 12 199.0 192.4 13 26.2 87.4 14 19.6 6.415 34.9 151.7 16 19.4 31.5 17 12.8 21.6 18 30.2 23.6 19 2.4 4.2 20 6.47.7 21 3.9 <1.0 22 <1.0 <1.0 23 <1.0 <1.0 24 13.7 6.1 25 <1.0 <1.0 2611.9 <1.0 27 <1.0 <1.0 28 1.6 6.4 29 51.2 105.5 30 80.7 76.7 31 1.1 7.432 36.2 12.7 33 12.6 7.2 34 4.2 4.6 35 26.3 22.6 36 341.2 426.8 37 32.442.7 38 20.8 — 39 22.8 — 40 2.5 1.9 41 398.7 314.6 42 179.9 112.5 43 3.64.6 44 71.3 57.7 45 9.8 23.5 46 68.9 24.2 47 4.9 16.6 48 3.4 13.2 49 2.511.7 50 1.5 5.3 51 2.2 2.0 52 5.7 7.8 53 7.8 19.1 54 4.7 7.9 55 8.8 18.756 9.3 14.1 Reference >1000 >1000 Compound

1. A compound of formula (I):

and/or a pharmaceutically acceptable salt thereof, wherein: Z¹ and Z² are independently selected from C and N; a

moiety is

R¹, R², and R⁵ are independently selected from: hydrogen, halogen, CN, nitro, NH₂, (CH₂)_(m)-Q, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, and wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₃₋₁₀ cycloalkyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R⁷; Q is selected from aryl, heteroaryl, C₃₋₁₀ cycloalkyl, and heterocyclyl, wherein aryl, heteroaryl, C₃₋₁₀ cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R⁸; R³, R⁴, and R⁶ are independently selected from: hydrogen, halogen, CN, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R⁷; each R⁷ is independently selected from: halogen, CN, nitro, C(═O)R^(b), C(═O)OR^(b), C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), OR^(a), OC(═O)R^(b), OC(═O)NR^(a)R^(a), OC₁₋₆ alkylN(R^(a))C(═O)OR^(b), OC(═O)N(R^(a))S(═O)₂R^(b), OC₂₋₆ alkylNR^(a)R^(a), OC₂₋₆ alkylOR^(a), SR^(a), S(═O)R^(b), S(═O)₂R^(b), S(═O)₂NR^(a)R^(a), S(═O)₂N(R^(a))C(═O)R^(b), S(═O)₂N(R^(a))C(═O)OR^(b), S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), (CR^(c)R^(c))_(n)NR^(a)R^(a), N(R^(a))C(═O)R^(b), N(R^(a))C(═O)OR^(b), N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(NR^(a))NR^(a)R^(a), N(R^(a))S(═O)₂R^(b), N(R^(a))S(═O)₂NR^(a)R^(a), NR^(a)C₂₋₆ alkylNR^(a)R^(a), NR^(a)C₂₋₆alkylOR^(a), (CR^(c)R^(c))_(n)C₄₋₈ heterocycloalkyl, (CR^(c)R^(c))_(n) aryl, (CR^(c)R^(c))_(n) heteroaryl, (CR^(c)R^(c))_(n)O(CR^(c)R^(c))_(n) aryl, (CR^(c)R^(c))_(n)C₃₋₈cycloalkyl, (CR^(c)R^(c))_(n)C₄₋₈ heterocycloalkyl, (CR^(c)R^(c))_(n)O(CR^(c)R^(c))_(n)CF₃, (CR^(c)R^(c))_(n) N(CR^(c)R^(c))_(n)OR^(a), (CR^(c)R^(c))_(n)N(R^(a))(CR^(c)R^(c))_(n) aryl, (CR^(c)R^(c))_(n)N(R^(a))(CR^(c)R^(c))_(n) heteroaryl, (CR^(c)R^(c))_(n)O(CR^(c)R^(c))_(n) heteroaryl, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, C₃₋₈ cycloalkyl and C₄₋₈ heterocycloalkyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from: halogen, oxo, C_(I-6) alkyl, CN, nitro, C(═O)R^(b), C(═O)OR^(b), C(═O)NR^(a)R^(a), C(NR^(a))NR^(a)R^(a), OR^(a), OC(═O)R^(b), OC(═O)NR^(a)R^(a), OC(═O)N(R^(a))S(═O)₂R^(b), OC₂₋₆ alkylNR^(a)R^(a), OC₂₋₆ alkylOR^(a), SR^(a), S(═O)R^(b), S(═O)₂R^(b), S(═O)₂NR^(a)R^(a), S(═O)₂N(R^(a))C(═O)R^(b), S(═O)₂N(R^(a))C(═O)OR^(b), S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), NR^(a)R^(a), N(R^(a))C(═O)R^(b), N(R^(a))C(═O)OR^(b), N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a), N(R^(a))S(═O)₂R^(b), N(R^(a))S(═O)₂NR^(a)R^(a), NR^(a)C₂₋₆alkylNR^(a)R^(a), NR^(a)C₂₋₆alkylOR^(a), N(R^(a))(CR^(a)R^(a))_(n)—Y, (CR^(a)R^(a))_(n)—Y, (CR^(a)R^(a))_(n)C₃₋₈ cycloalkyl, and (CR^(a)R^(a))_(n)OR^(a); each R⁸ is independently selected from: halogen, oxo, OCHF₂, OCF₃, CN, nitro, C(═O)R^(b), C(═O)OR^(b), C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), OR^(a), OC(═O)R^(b), OC(═O)NR^(a)R^(a), OC₁₋₆ alkylN(R^(a))C(═O)OR^(b), OC(═O)N(R^(a))S(═O)₂R^(b), OC₂₋₆ alkylNR^(a)R^(a), OC₂₋₆ alkylOR^(a), SR^(a), S(═O)R^(b), S(═O)₂R^(b), S(═O)₂NR^(a)R^(a), S(═O)₂N(R^(a))C(═O)R^(b), S(═O)₂N(R^(a))C(═O)OR^(b), S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), NR^(a)R^(a), N(R^(a))C(═O)R^(b), N(R^(a))C(═O)OR^(b), N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a), N(R^(a))S(═O)₂R^(b), N(R^(a))S(═O)₂NR^(a)R^(a), NR^(a)C₂₋₆alkylNR^(a)R^(a), NR^(a)C₂₋₆ alkylOR^(a), C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from: halogen, CN, nitro, C(═O)R^(b), C(═O)OR^(b), C(═O)NR^(a)R^(a), C(═NR^(a))NR^(a)R^(a), OR^(a), OC(═O)R^(b), OC(═O)NR^(a)R^(a), OC(═O)N(R^(a))S(═O)₂R^(b), OC₂₋₆ alkylNR^(a)R^(a), OC₂₋₆ alkylOR^(a), SR^(a), S(═O)R^(b), S(═O)₂R^(b), S(═O)₂NR^(a)R^(a), S(═O)₂N(R^(a))C(═O)R^(b), S(═O)₂N(R^(a))C(═O)OR^(b), S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), NR^(a)R^(a), N(R^(a))C(═O)R^(b), N(R^(a))C(═O)OR^(b), N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a), N(R^(a))S(═O)₂R^(b), N(R^(a))S(═O)₂NR^(a)R^(a), NR^(a)C₂₋₆ alkylNR^(a)R^(a), NR^(a)C₂₋₆ alkylOR^(a), N(R^(a))(CR^(a)R^(a))_(n)—Y, (CR^(a)R^(a))_(n)—Y, and (CR^(a)R^(a))_(n)OR^(a); each R^(a) is independently selected from hydrogen and R^(b); each R^(b) is independently selected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, C₃₋₈ cycloalkyl, and C₄₋₈ heterocycloalkyl, wherein the C_(I-6) alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, C₃₋₈ cycloalkyl and C₄₋₈ heterocycloalkyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from: halogen, CN, OH, S(═O)₂R^(b), OC₂₋₆ alkylOR^(a), C_(I-4) alkyl, C_(I-3) haloalkyl, OC_(I-4) alkyl, NH₂, and NR^(a)R^(a); or R^(a) and R^(b) together with the carbon atoms and/or heteroatoms to which they are attached can form a 4-10 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from sulfur and nitrogen; each R^(c) is independently selected from: hydrogen, OR^(a), NR^(a)R^(a), C_(I-6) alkyl, and CR^(c)R^(c) can form a C₃₋₈ cycloalkyl ring; Y is selected from: aryl, heteroaryl, C₃₋₁₀ cycloalkyl, and heterocyclyl, wherein aryl, heteroaryl, C₃₋₁₀ cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from: C₁₋₈ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C_(I-4) haloalkyl, halogen, CN, nitro, C(═O)R^(b), C(═O)OR^(b), C(═O)NR^(a)R^(a), C(NR^(a))NR^(a)R^(a), OR^(a), OC(═O)R^(b), OC(═O)NR^(a)R^(a), OC(═O)N(R^(a))S(═O)₂R^(b), OC₂₋₆ alkylNR^(a)R^(a), OC₂₋₆ alkylOR^(a), SR^(a), S(═O)R^(b), S(═O)₂R^(b), S(═O)₂NR^(a)R^(a), S(═O)₂N(R^(a))C(═O)R^(b), S(═O)₂N(R^(a))C(═O)OR^(b), S(═O)₂N(R^(a))C(═O)NR^(a)R^(a), NR^(a)R^(a), N(R^(a))C(═O)R^(b), N(R_(a))C(═O)OR^(b), N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))C(═NR^(a))NR^(a)R^(a), N(R^(a))S(═O)₂R^(b), N(R^(a))S(═O)₂NR^(a)R^(a), NR^(a)C₂₋₆alkylNR^(a)R^(a), and NR^(a)C₂₋₆ alkylOR^(a); each m is selected from 0, 1, 2, 3, and 4, each n is independently selected from 0, 1, 2, and
 3. 2. A compound of claim 1, and/or a pharmaceutically acceptable salt thereof, wherein: a

moiety is


3. A compound of claim 1, and/or a pharmaceutically acceptable salt thereof, wherein R⁶ is hydrogen.
 4. A compound of claim 1, and/or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl and C₃₋₁₀ cycloalkyl, wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from halogen and OR^(a), wherein R^(a) is independently selected from hydrogen and C₁₋₆ alkyl.
 5. A compound of claim 4, and/or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl, ethyl, propyl, isopropyl, allyl, or cyclopropyl, each is independently unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from halogen and OR^(a), wherein R^(a) is independently selected from hydrogen and C₁₋₆ alkyl.
 6. A compound of claim 5, and/or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl, ethyl, propyl, isopropyl, allyl, or cyclopropyl, each is independently unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from halogen and OR^(a), wherein R^(a) is independently selected from hydrogen and methyl.
 7. A compound of claim 6, and/or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl, ethyl, propyl, isopropyl, allyl, cyclopropyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,3-dihydroxypropyl, or 2-methoxyethyl.
 8. A compound of claim 1, and/or a pharmaceutically acceptable salt thereof, wherein R² is selected from hydrogen, halogen, CN, (CH₂)_(m)-Q, C₁₋₆ alkyl, or C_(m) cycloalkyl, wherein alkyl and cycloalkyl are independently unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R⁷.
 9. A compound of claim 8, and/or a pharmaceutically acceptable salt thereof, wherein R² is selected from (CH₂)_(m)-Q, wherein m is 0, and Q is selected from aryl and heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R⁸.
 10. A compound of claim 9, and/or a pharmaceutically acceptable salt thereof, wherein R² is selected from (CH₂)_(m)-Q, wherein m is 0, and Q is phenyl, which is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R⁸, which is independently selected from NR^(a)R^(a), N(R^(a))C(═O)R^(b), N(R^(a))C(═O)OR^(b), N(R^(a))C(═O)NR^(a)R^(a), N(R^(a))S(═O)₂R^(b), N(R^(a))S(═O)₂NR^(a)R^(a).
 11. A compound of claim 10, and/or a pharmaceutically acceptable salt thereof, wherein R² is selected from (CH₂)_(m)-Q, wherein m is 0, and Q is phenyl which is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R⁸, wherein R⁸ is independently selected from N(R^(a))C(═O)R^(b), N(R^(a))S(═O)₂R^(b), wherein R^(a) is hydrogen or methyl, and R^(b) is independently selected from methyl, ethyl, isopropyl and cyclopropyl.
 12. A compound of claim 10, and/or a pharmaceutically acceptable salt thereof, wherein R^(a) and R^(b) together with the carbon atoms and/or heteroatoms to which they are attached form a 5-6 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from sulfur and nitrogen.
 13. A compound of claim 10, and/or a pharmaceutically acceptable salt thereof, wherein Q is phenyl which is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R⁸, wherein R⁸ is independently selected from 2-oxopyrrolidin-1-yl and 1,1-dioxidoisothiazolidin-2-yl.
 14. A compound of claim 1, and/or a pharmaceutically acceptable salt thereof, wherein R³ is C₁₋₆ alkyl.
 15. A compound of claim 14, and/or a pharmaceutically acceptable salt thereof, wherein R³ is methyl.
 16. A compound of claim 1, and/or a pharmaceutically acceptable salt thereof, wherein R⁴ is selected from hydrogen, halogen and C₁₋₆ alkyl.
 17. A compound of claim 16, and/or a pharmaceutically acceptable salt thereof, wherein R⁴ is selected from halogen and methyl.
 18. A compound of claim 17, and/or a pharmaceutically acceptable salt thereof, wherein R⁴ is fluorine or chlorine.
 19. A compound of claim 1, and/or a pharmaceutically acceptable salt thereof, wherein R⁵ is (CH₂)_(m)-Q, wherein m is 0 and Q is aryl which is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R⁸.
 20. A compound of claim 19, and/or a pharmaceutically acceptable salt thereof, wherein R⁵ is (CH₂)_(m)-Q, wherein m is 0 and Q is phenyl which is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from halogen.
 21. A compound of claim 20, and/or a pharmaceutically acceptable salt thereof, wherein R⁵ is 2-fluoro-4-iodophenyl or 4-bromo-2-fluorophenyl.
 22. A compound of claim 1, selected from: N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide, N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propionamide, N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)isobutyramide, N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanecarboxamide, N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide, N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)ethanesulfonamide, N-(3-(6-cyclopropyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide, N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propionamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)isobutyramide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanecarboxamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)ethanesulfonamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-isopropyl-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-6-propyl-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-(2-methoxyethyl)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-6-(2-fluoroethyl)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide, N-(3-(6-(2,2-difluoroethyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide, N-(3-(3-fluoro-4-(2-fluoro-4-iodophenylamino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide, N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide, N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide, N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide, N-(3-(6-ethyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide, N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide, N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propionamide, N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanecarboxamide, N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide, N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)ethanesulfonamide, N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide, N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanesulfonamide, N-(3-(6-allyl-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)isobutyramide, N-(3-(6-allyl-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide, N-(3-(6-allyl-4-(4-bromo-2-fluorophenylamino)-3-fluoro-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide, N-(3-(6-allyl-3-chloro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide, N-(3-(3-chloro-6-(2,3-dihydroxypropyl)-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide, N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)acetamide, N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propionamide, N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)cyclopropanecarboxamide, N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)methanesulfonamide, N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)ethanesulfonamide, N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide, N-(3-(6-(2,3-dihydroxypropyl)-3-fluoro-4-(2-fluoro-4-iodophenylamino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)propane-2-sulfonamide, N-(3-(6-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylmethanesulfonamide, N-(3-(6-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylpropane-2-sulfonamide, N-(3-(6-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylcyclopropanesulfonamide, N-(3-(3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylmethanesulfonamide, N-(3-(3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylpropane-2-sulfonamide, N-(3-(3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-2,5-dioxo-1,2,5,6-tetrahydropyrido[2,3-d]pyridazin-8-yl)phenyl)-N-methylcyclopropanesulfonamide, 6-cyclopropyl-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methyl-8-(3-(2-oxopyrrolidin-1-yl)phenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione, 3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethyl-8-(3-(2-oxopyrrolidin-1-yl)phenyl)pyrido[2,3-d]pyridazine-2,5(1H,6H)-dione, 6-cyclopropyl-8-(3-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1-methylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione, and 8-(3-(1,1-dioxidoisothiazolidin-2-yl)phenyl)-3-fluoro-4-((2-fluoro-4-iodophenyl)amino)-1,6-dimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione.
 23. A pharmaceutical composition, comprising a compound of claim 1, and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
 24. A method for modulating MEK, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, and/or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 25-28. (canceled) 